The DOI matches its Crossref record; 223 of the 223 references it cites were found in a registry or an index; 8 of the 201 sources its claims cite were checked for support.
Advances in covalent drug discovery
Open accessAbstract
Covalent drugs have been used to treat diseases for more than a century, but tools that facilitate the rational design of covalent drugs have emerged more recently. The purposeful addition of reactive functional groups to existing ligands can enable potent and selective inhibition of target proteins, as demonstrated by the covalent epidermal growth factor receptor (EGFR) and Bruton’s tyrosine kinase (BTK) inhibitors used to treat various cancers. Moreover, the identification of covalent ligands through ‘electrophile-first’ approaches has also led to the discovery of covalent drugs, such as covalent inhibitors for KRAS(G12C) and SARS-CoV-2 main protease. In particular, the discovery of KRAS(G12C) inhibitors validates the use of covalent screening technologies, which have become more powerful and widespread over the past decade. Chemoproteomics platforms have emerged to complement covalent ligand screening and assist in ligand discovery, selectivity profiling and target identification. This Review showcases covalent drug discovery milestones with emphasis on the lessons learned from these programmes and how an evolving toolbox of covalent drug discovery techniques facilitates success in this field. The rational discovery of covalent drugs depends on an expanding toolset of techniques. Here, Daniel Nomura and colleagues highlight covalent drugs that have achieved success over the past decade and discuss the tools and strategies that facilitate their discovery, describing two complementary approaches, namely, ligand-first and electrophile-first strategies.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
This review traces covalent drug discovery from serendipitous historical agents to rational ligand-first and electrophile-first programmes, highlighting approved inhibitors for EGFR, BTK, KRAS(G12C), SARS-CoV-2 Mpro and other targets. It argues that chemoproteomics, covalent screening and structure-guided design now form an integrated toolbox for tackling previously undruggable proteins.
Key findings
- Covalent drugs can gain potency and selectivity by adding mildly reactive electrophiles to reversible ligands or by screening electrophilic libraries; examples include osimertinib and ibrutinib, with 2020 sales of US$8.43 billion and US$4.33 billion respectively, and sotorasib, approved in 2021 for KRASG12C-mutated NSCLC.
- Electrophile-first discovery was validated by KRAS(G12C) inhibitors: an initial tethering screen of 480 disulfide fragments and later a 3,300-acrylamide screen contributed to sotorasib; KRAS is mutated in about 25% of cancers, and KRASG12C accounts for 12–14% of KRAS mutations in NSCLC.
- Covalent protease inhibitors include nirmatrelvir, which forms a reversible covalent nitrile adduct with SARS-CoV-2 Mpro Cys145 and was authorized as part of Paxlovid in December 2021; HCV NS3/4a ketoamide inhibitors boceprevir and telaprevir were approved in 2011 but later discontinued or withdrawn.
- Chemoproteomic platforms such as isoTOP-ABPP and SLC-ABPP enable profiling of more than 30,000 reactive cysteines, over 8,000 cysteine sites in 18 min per compound, and show that 97% of E3 ligases possess reactive cysteines, supporting covalent E3 recruiters for targeted protein degradation.
Methods
- Narrative review, not primary research; it synthesizes published literature, drug approval histories, structural biology and chemoproteomic datasets across covalent drug discovery.
- Evidence is organized by discovery approach: ligand-first (EGFR, BTK and other kinases), electrophile-first (KRAS(G12C), SARS-CoV-2 Mpro, HCV protease, proteasome, boron-containing drugs, voxelotor) and enabling tools (screening platforms, chemoproteomics, covalent docking).
- Includes tables comparing key covalent drugs and screening methods, plus figures on development timelines, inhibitor–target structures and isoTOP-ABPP workflow; no systematic search strategy or meta-analysis is described.
Limitations
- The paper states no explicit limitations. Evident: it is a selective narrative review without systematic search criteria or quantitative synthesis, so examples are chosen to illustrate milestones rather than exhaustively cover the field.
- Evident: many claims depend on cited primary studies and clinical or preclinical data that are not independently reanalysed, and the fast-moving nature of the field may date some coverage.
- Evident: the review emphasizes cysteine-targeting electrophiles and oncology or infectious disease examples, with comparatively less attention to non-cysteine nucleophilic residues and other covalent strategies.
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Claims the paper makes
130 Not checked yet · 29 Own interpretation · 14 No basis given · 6 Supported · 1 Couldn’t confirm · accuracy not yet measured
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“Nirmatrelvir (Table 1) covalently inhibits the Mpro of SARS-CoV-2 (ref.3).”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > SARS-CoV-2 main protease inhibitors
What the sources say
- Could not verifycites [3] Ghosh, A. K., Samanta, I., Mondal, A. & Liu, W. R. Covalent inhibition in drug discovery. ChemMedChem 14, 889–906 (2019). sourceExperimental — accuracy not yet measured
The sections on covalent inhibitors for KRAS mutants and the Introduction discuss other inhibitors, but do not address nirmatrelvir or SARS-CoV-2 main protease. Searches for those names and for coronavirus protease inhibitors found no passage supporting the attributed claim. Page numbers were not supplied in our copy. (LLM, conf=0.75)
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Every source the paper cites for this claim was checked and supports it.
In the paper
“Viral replication depends on successful cleavage of pp1a and pp1ab by the Mpro (also referred to as 3CLpro), which is a cysteine protease, into functional viral proteins100.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > SARS-CoV-2 main protease inhibitors
What the sources say
- Supportedcites [100] Qiao, J. et al. SARS-CoV-2 Mpro inhibitors with antiviral activity in a transgenic mouse model. Science 371, 1374–1378 (2021). source
The passage labeled Abstract states that cleavage of pp1a and pp1ab into nonstructural proteins is essential for viral genome replication and identifies Mpro (3CL protease) as one of the proteases that performs it. The paper also identifies Cys145 as a catalytic residue, consistent with the description of Mpro as a cysteine protease. (LLM, conf=0.92)
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In the paper
“but covalent binding can be maintained by replacing the disulfide with an electrophile such as an acrylamide, as in the case of the initial covalent KRAS(G12C) inhibitors88.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Screening platforms
What the sources say
- Supportedcites [88] Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A. & Shokat, K. M. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503, 548–551 (2013). This work showcases the use of tethering as a screening methodology for discovering covalent ligands against KRAS(G12C) and further identifies ligands against this oncogenic protein. source
The paper describes using a disulphide-fragment tethering screen to identify a starting compound, then turning to carbon-based electrophiles, including acrylamides, for irreversible cysteine bond formation (Abstract; page not supplied). This supports the cited example of maintaining covalent binding in the initial K-Ras(G12C) inhibitors. (LLM, conf=0.94)
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In the paper
“In both cases, covalent engagement of a cysteine residue disrupted a protein–protein interaction to modulate immune cell function.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Supportedcites [184] Blewett, M. M. et al. Chemical proteomic map of dimethyl fumarate–sensitive cysteines in primary human T cells. Sci. Signal. 9, rs10 (2016). source
The Results section reports that DMF disrupts a cysteine motif in PKCθ that regulates its interaction with CD28, impairing T-cell activation. This supports the case attributed to this paper; the paper does not need to establish the citing sentence’s other case. (LLM, conf=0.91)
- Supportedcites [185] Zaro, B. W. et al. Dimethyl fumarate disrupts human innate immune signaling by targeting the IRAK4–MyD88 complex. J. Immunol. 202, 2737–2746 (2019). source
The Introduction reports that DMF modifies cysteine 13 of IRAK4, disrupting MyD88 binding and IRAK4 function. The Results section “DMF disrupts IRAK4-MYD88 interactions” further reports that DMF blocked the interaction, but not when IRAK4 carried a C13A mutation. This supports the case documented by the cited paper; the sentence’s other case is not identified here. (LLM, conf=0.91)
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Of ~9,200 cysteine sites identified, BTK Cys481 was one of the cysteines most liganded by ibrutinib.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Supportedcites [183] Kuljanin, M. et al. Reimagining high-throughput profiling of reactive cysteines for cell-based screening of large electrophile libraries. Nat. Biotechnol. 39, 630–641 (2021). source
The Results section, “Benchmarking SLC-ABPP using cysteine-reactive lead compounds,” states that BTK cysteine-481 was one of the most significantly liganded sites among approximately 9,200 cysteine sites after ibrutinib treatment. The experiment used spleen tissue from treated mice; the passage provides no page number. (LLM, conf=0.95)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Cys313 on B lymphocyte kinase (BLK), which, analogous to BTK, contains a cysteine within the ATP-binding pocket, was also identified as an off-target of ibrutinib183.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Supportedcites [183] Kuljanin, M. et al. Reimagining high-throughput profiling of reactive cysteines for cell-based screening of large electrophile libraries. Nat. Biotechnol. 39, 630–641 (2021). source
In Results, under “Benchmarking SLC-ABPP using cysteine-reactive lead compounds,” the paper identifies BTK cysteine-481 as liganded by ibrutinib and BLK cysteine-313 as another ibrutinib target. It also states that BLK has a cysteine in the ATP-binding pocket analogous to BTK. (LLM, conf=0.94)
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In the paper
“This ‘electrophile-first’ approach is partly facilitated by the development of chemoproteomic platforms that enable rapid target identification and selectivity profiling of covalent ligands14–18.”
§ Advances in covalent drug discovery > Introduction
What the sources say
- Not checked yetcites [14] Spradlin, J. N., Zhang, E. & Nomura, D. K. Reimagining druggability using chemoproteomic platforms. Acc. Chem. Res. 54, 1801–1813 (2021). source
- Not checked yetcites [15] Roberts, A. M., Ward, C. C. & Nomura, D. K. Activity-based protein profiling for mapping and pharmacologically interrogating proteome-wide ligandable hotspots. Curr. Opin. Biotechnol. 43, 25–33 (2017). source
- Not checked yetcites [16] Drewes, G. & Knapp, S. Chemoproteomics and chemical probes for target discovery. Trends Biotechnol. 36, 1275–1286 (2018). source
- Not checked yetcites [17] Moellering, R. E. & Cravatt, B. F. How chemoproteomics can enable drug discovery and development. Chem. Biol. 19, 11–22 (2012). source
- Not checked yetcites [18] Maurais, A. J. & Weerapana, E. Reactive-cysteine profiling for drug discovery. Curr. Opin. Chem. Biol. 50, 29–36 (2019). source
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In the paper
“Afatinib (Boehringer Ingelheim) (Figs. 1 and 2b) was approved by the FDA in 2013 as a first-line treatment for patients with metastatic NSCLC with activating mutations in EGFR37,38.”
§ Advances in covalent drug discovery > Discoveries by ligand-first approaches > Covalent EGFR inhibitors
What the sources say
- Not checked yetcites [37] Soria, J.-C. et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol. 16, 897–907 (2015). source
- Not checked yetcites [38] Yu, H. A. & Pao, W. Afatinib — new therapy option for EGFR-mutant lung cancer. Nat. Rev. Clin. Oncol. 10, 551–552 (2013). source
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In the paper
“The prolonged target engagement of covalent drugs can provide distinct pharmacodynamic profiles and exceptional potency6.”
§ Advances in covalent drug discovery > Introduction
What the sources say
- Not checked yetcites [6] Zhang, T., Hatcher, J. M., Teng, M., Gray, N. S. & Kostic, M. Recent advances in selective and irreversible covalent ligand development and validation. Cell Chem. Biol. 26, 1486–1500 (2019). source
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In the paper
“Covalent ligand screening is another ligand discovery approach that is becoming more common, whereby various methods are used to discover covalent ligands from libraries of electrophilic compounds7,12,13.”
§ Advances in covalent drug discovery > Introduction
What the sources say
- Not checked yetcites [7] Lonsdale, R. & Ward, R. A. Structure-based design of targeted covalent inhibitors. Chem. Soc. Rev. 47, 3816–3830 (2018). source
- Not checked yetcites [12] Lagoutte, R., Patouret, R. & Winssinger, N. Covalent inhibitors: an opportunity for rational target selectivity. Curr. Opin. Chem. Biol. 39, 54–63 (2017). source
- Not checked yetcites [13] Lu, W. et al. Fragment-based covalent ligand discovery. RSC Chem. Biol. 2, 354–367 (2021). source
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In the paper
“in 60% of cases this was due to the acquisition of the T790M ‘gatekeeper mutation’34,35.”
§ Advances in covalent drug discovery > Discoveries by ligand-first approaches > Covalent EGFR inhibitors
What the sources say
- Not checked yetcites [34] Yu, H. A. et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR -mutant lung cancers. Clin. Cancer Res. 19, 2240–2247 (2013). source
- Not checked yetcites [35] Recondo, G., Facchinetti, F., Olaussen, K. A., Besse, B. & Friboulet, L. Making the first move in EGFR-driven or ALK-driven NSCLC: first-generation or next-generation TKI? Nat. Rev. Clin. Oncol. 15, 694–708 (2018). source
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In the paper
“During clinical development in the early 2000s, the reversible, first-generation EGFR inhibitors gefitinib and erlotinib (Fig. 2a) were discovered to be effective against tumours harbouring somatic activating mutations in EGFR, either deletions in exon 19 or the L858R point mutation, which occur in 10–30% of patients with NSCLC31–33.”
§ Advances in covalent drug discovery > Discoveries by ligand-first approaches > Covalent EGFR inhibitors
What the sources say
- Not checked yetcites [31] Lynch, T. J., Okimoto, R. A., Supko, J. G. & Settleman, J. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non–small-cell lung cancer to gefitinib. N. Engl. J. Med. 350, 2129–2139 (2004). source
- Not checked yetcites [32] Paez, J. G. et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304, 1497–1500 (2004). source
- Not checked yetcites [33] Ou, S.-H. I. Second-generation irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs): a better mousetrap? A review of the clinical evidence. Crit. Rev. Oncol. Hematol. 83, 407–421 (2012). source
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In the paper
“Historically, concerns about the interference of these reactive molecules with biological assays and potential lack of selectivity often discouraged further investigation2,3.”
§ Advances in covalent drug discovery > Introduction
What the sources say
- Not checked yetcites [2] Singh, J., Petter, R. C., Baillie, T. A. & Whitty, A. The resurgence of covalent drugs. Nat. Rev. Drug Discov. 10, 307–317 (2011). This review illustrates the key features of covalent drug discovery with emphasis on targeted covalent inhibitors. source
- Not checked yetcites [3] Ghosh, A. K., Samanta, I., Mondal, A. & Liu, W. R. Covalent inhibition in drug discovery. ChemMedChem 14, 889–906 (2019). source
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In the paper
“Despite the increased potency that covalent engagement brought against the disease target, the dose-limiting toxicity caused by inhibition of wild-type EGFR likely prevented afatinib from increasing overall survival when compared head-to-head with platinum-based chemotherapy in treating cancers bearing the T790M gatekeeper mutation39.”
§ Advances in covalent drug discovery > Discoveries by ligand-first approaches > Covalent EGFR inhibitors
What the sources say
- Not checked yetcites [39] Harvey, R. D., Adams, V. R., Beardslee, T. & Medina, P. Afatinib for the treatment of EGFR mutation-positive NSCLC: a review of clinical findings. J. Oncol. Pharm. Pract. 26, 1461–1474 (2020). source
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In the paper
“Third, 12–14% of KRAS mutations in NSCLC are KRASG12C, presenting a promising patient group that would directly benefit from KRAS(G12C) inhibition89.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Covalent KRAS(G12C) inhibitors
What the sources say
- Not checked yetcites [89] Hofmann, M. H., Gerlach, D., Misale, S., Petronczki, M. & Kraut, N. Expanding the reach of precision oncology by drugging all KRAS mutants. Cancer Discov. 12, 924–937 (2022). source
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In the paper
“Since the discovery of the role of KRAS in cancer nearly 30 years ago, attempts to drug it directly using traditional drug discovery methods have been unsuccessful9,10.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Covalent KRAS(G12C) inhibitors
What the sources say
- Not checked yetcites [9] Moore, A. R., Rosenberg, S. C., McCormick, F. & Malek, S. RAS-targeted therapies: is the undruggable drugged? Nat. Rev. Drug Discov. 19, 533–552 (2020). source
- Not checked yetcites [10] Huang, L., Guo, Z., Wang, F. & Fu, L. KRAS mutation: from undruggable to druggable in cancer. Signal Transduct. Target. Ther. 6, 386 (2021). source
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In the paper
“Paxlovid was shown to be highly effective at preventing progression to severe COVID-19 in symptomatic patients105.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > SARS-CoV-2 main protease inhibitors
What the sources say
- Not checked yetcites [105] Hammond, J. et al. Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19. N. Engl. J. Med. 386, 1397–1408 (2022). source
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In the paper
“The discovery of covalent inhibitors against SARS-CoV-2 Mpro emerged from extensive work on protease inhibitors for SARS-CoV-1, which is the causative virus for severe acute respiratory syndrome coronavirus 1 (SARS1)100.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > SARS-CoV-2 main protease inhibitors
What the sources say
- Not checked yetcites [100] Qiao, J. et al. SARS-CoV-2 Mpro inhibitors with antiviral activity in a transgenic mouse model. Science 371, 1374–1378 (2021). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“the oral bioavailability of PF-00835231 was improved by replacing the α-hydroxymethylketone moiety with a nitrile group, which can also act as an electrophile103.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > SARS-CoV-2 main protease inhibitors
What the sources say
- Not checked yetcites [103] Owen, D. R. et al. An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19. Science 374, 1586–1593 (2021). This work describes the discovery of PF-07321332, later named nirmatrelvir, an orally bioavailable SARS-CoV-2 Mpro inhibitor. source
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In the paper
“Generally, when reactive cysteine residues are shared across a protein family, structurally guided adaptation of previously studied cysteine-reactive covalent inhibitors can lead to selective and potent drugs for other proteins with this feature.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > SARS-CoV-2 main protease inhibitors
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In the paper
“α-Ketoamide-based covalent inhibitors have been developed to treat hepatitis C virus (HCV) infection through inhibiting NS3/4a”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > HCV NS3/4a protease inhibitors
What the sources say
- Not checked yetcites [107] de Leuw, P. & Stephan, C. Protease inhibitor therapy for hepatitis C virus-infection. Expert. Opin. Pharmacother. 19, 577–587 (2018). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Generally, drugs whose efficacy relies on covalent binding to a specific nucleophilic amino acid are vulnerable to mutations at that site, which could lead to drug resistance.”
§ Advances in covalent drug discovery > Discoveries by ligand-first approaches > Covalent EGFR inhibitors
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In the paper
“NS3/4a — a serine protease that cleaves the HCV polyprotein into multiple non-structural proteins required for replication107.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > HCV NS3/4a protease inhibitors
What the sources say
- Not checked yetcites [107] de Leuw, P. & Stephan, C. Protease inhibitor therapy for hepatitis C virus-infection. Expert. Opin. Pharmacother. 19, 577–587 (2018). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“BTK became a target of interest in chronic lymphocytic leukaemia owing to its crucial role downstream of the B cell receptor53.”
§ Advances in covalent drug discovery > Discoveries by ligand-first approaches > Covalent BTK inhibitors
What the sources say
- Not checked yetcites [53] Pal Singh, S., Dammeijer, F. & Hendriks, R. W. Role of Bruton’s tyrosine kinase in B cells and malignancies. Mol. Cancer 17, 57 (2018). source
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In the paper
“The in vivo efficacy of nirmatrelvir was demonstrated in a mouse-adapted SARS-CoV-2 (SARS-CoV-2 MA10) model.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > SARS-CoV-2 main protease inhibitors
What the sources say
- Not checked yetcites [103] Owen, D. R. et al. An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19. Science 374, 1586–1593 (2021). This work describes the discovery of PF-07321332, later named nirmatrelvir, an orally bioavailable SARS-CoV-2 Mpro inhibitor. source
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In the paper
“Covalent targeting of the non-conserved Cys909 of JAK3 has yielded inhibitors selective for JAK3 over other JAK family members for the treatment of autoimmune diseases77–81.”
§ Advances in covalent drug discovery > Discoveries by ligand-first approaches > Other covalent kinase inhibitors
What the sources say
- Not checked yetcites [77] Thorarensen, A. et al. Design of a Janus kinase 3 (JAK3) specific inhibitor 1-((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one (PF-06651600) allowing for the interrogation of JAK3 signaling in humans. J. Med. Chem. 60, 1971–1993 (2017). source
- Not checked yetcites [78] Goedken, E. R. et al. Tricyclic covalent inhibitors selectively target Jak3 through an active site thiol. J. Biol. Chem. 290, 4573–4589 (2015). source
- Not checked yetcites [79] Tan, L. et al. Development of selective covalent Janus kinase 3 inhibitors. J. Med. Chem. 58, 6589–6606 (2015). source
- Not checked yetcites [80] Kempson, J. et al. Discovery of highly potent, selective, covalent inhibitors of JAK3. Bioorg. Med. Chem. Lett. 27, 4622–4625 (2017). source
- Not checked yetcites [81] Telliez, J.-B. et al. Discovery of a JAK3-selective inhibitor: functional differentiation of JAK3-selective inhibition over pan-JAK or JAK1-selective inhibition. ACS Chem. Biol. 11, 3442–3451 (2016). source
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In the paper
“The quick adaptation of previous protease inhibitors to selectively target SARS-CoV-2 Mpro is an example of using structure-based design while taking into account the valuable properties of covalent drugs.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > SARS-CoV-2 main protease inhibitors
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In the paper
“Nitriles can covalently bind particularly reactive nucleophiles; however, the ease of thiol elimination from the thioimidate adduct makes nitriles more reversible than some other electrophiles, such as acrylamides104.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > SARS-CoV-2 main protease inhibitors
What the sources say
- Not checked yetcites [104] Bandyopadhyay, A. & Gao, J. Targeting biomolecules with reversible covalent chemistry. Curr. Opin. Chem. Biol. 34, 110–116 (2016). source
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In the paper
“PF-07321332, named nirmatrelvir (Fig. 4 and Table 1), which is a highly potent SARS-CoV-2 reversible covalent inhibitor”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > SARS-CoV-2 main protease inhibitors
What the sources say
- Not checked yetcites [103] Owen, D. R. et al. An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19. Science 374, 1586–1593 (2021). This work describes the discovery of PF-07321332, later named nirmatrelvir, an orally bioavailable SARS-CoV-2 Mpro inhibitor. source
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In the paper
“The nitrile group of nirmatrelvir (shown in green) reacts with Cys145 of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (shown in light blue) to form a covalent thioimidate adduct.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > SARS-CoV-2 main protease inhibitors
What the sources say
- Not checked yetcites [103] Owen, D. R. et al. An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19. Science 374, 1586–1593 (2021). This work describes the discovery of PF-07321332, later named nirmatrelvir, an orally bioavailable SARS-CoV-2 Mpro inhibitor. source
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In the paper
“the ease of thiol elimination from the thioimidate adduct makes nitriles more reversible than some other electrophiles, such as acrylamides104.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > SARS-CoV-2 main protease inhibitors
What the sources say
- Not checked yetcites [104] Bandyopadhyay, A. & Gao, J. Targeting biomolecules with reversible covalent chemistry. Curr. Opin. Chem. Biol. 34, 110–116 (2016). source
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In the paper
“The rapid clearance of ibrutinib (which has a half-life of 2–3 h) could also enable kinase selectivity; ibrutinib should maintain activity against BTK owing to prolonged covalent engagement, while the reversible inhibition of off-targets is minimized65.”
§ Advances in covalent drug discovery > Discoveries by ligand-first approaches > Covalent BTK inhibitors
What the sources say
- Not checked yetcites [65] Advani, R. H. et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J. Clin. Oncol. 31, 88–94 (2013). source
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In the paper
“The inhibitor (compound 12 in their study) was discovered through a disulfide-fragment screening approach known as tethering, whereby a library of 480 disulfide fragments was screened against KRAS(G12C) in the GDP-bound state using intact protein mass spectrometry (MS)88,90.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Covalent KRAS(G12C) inhibitors
What the sources say
- Not checked yetcites [88] Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A. & Shokat, K. M. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503, 548–551 (2013). This work showcases the use of tethering as a screening methodology for discovering covalent ligands against KRAS(G12C) and further identifies ligands against this oncogenic protein. source
- Not checked yetcites [90] Erlanson, D. A., Wells, J. A. & Braisted, A. C. Tethering: fragment-based drug discovery. Annu. Rev. Biophys. Biomol. Struct. 33, 199–223 (2004). source
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In the paper
“PF-00835231, which demonstrated potent SARS-CoV-2 Mpro inhibition in an activity assay based on fluorescence resonance energy transfer (FRET)”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > SARS-CoV-2 main protease inhibitors
What the sources say
- Not checked yetcites [103] Owen, D. R. et al. An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19. Science 374, 1586–1593 (2021). This work describes the discovery of PF-07321332, later named nirmatrelvir, an orally bioavailable SARS-CoV-2 Mpro inhibitor. source
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In the paper
“The success of covalent EGFR inhibitors has validated the approach of covalently engaging non-catalytic, non-conserved cysteines adjacent to kinase active sites to increase the potency and modulate the pharmacodynamics of initially reversible ligands.”
§ Advances in covalent drug discovery > Discoveries by ligand-first approaches > Covalent EGFR inhibitors
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In the paper
“These shared features enabled the discovery of potent JAK3-selective covalent inhibitors using an EGFR inhibitor as a starting point”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > SARS-CoV-2 main protease inhibitors
What the sources say
- Not checked yetcites [79] Tan, L. et al. Development of selective covalent Janus kinase 3 inhibitors. J. Med. Chem. 58, 6589–6606 (2015). source
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In the paper
“Although half-maximal inhibitory concentration (IC50) values are often used to measure the potency of covalent inhibitors, the kinact/Ki second-order rate constant (where Ki is the inhibition constant and kinact is the rate of enzyme inactivation) is preferred because it describes inhibitor potency in a time-independent manner212,213.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox
What the sources say
- Not checked yetcites [212] Strelow, J. M. A perspective on the kinetics of covalent and irreversible inhibition. SLAS Discov. 22, 3–20 (2017). source
- Not checked yetcites [213] McWhirter, C. in Annual Reports in Medicinal Chemistry (eds Ward, R. A. & Grimster, N. P.) vol. 56 1–31 (Elsevier, 2021).
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In the paper
“ABPP was pioneered by Cravatt and Bogyo using active-site-directed chemical probes that covalently target catalytic residues of various enzyme classes, including hydrolases, proteases and kinases173,174.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [173] Cravatt, B. F., Wright, A. T. & Kozarich, J. W. Activity-based protein profiling: from enzyme chemistry to proteomic chemistry. Annu. Rev. Biochem. 77, 383–414 (2008). This review highlights the tools involved in ABPP and explains their corresponding applications. source
- Not checked yetcites [174] Edgington, L. E., Verdoes, M. & Bogyo, M. Functional imaging of proteases: recent advances in the design and application of substrate-based and activity-based probes. Curr. Opin. Chem. Biol. 15, 798–805 (2011). source
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In the paper
“These compounds, along with narlaprevir113, use a ketoamide electrophile to covalently engage the catalytic serine of NS3/4a.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > HCV NS3/4a protease inhibitors
What the sources say
- Not checked yetcites [113] Arasappan, A. et al. Discovery of narlaprevir (SCH 900518): a potent, second generation HCV NS3 serine protease inhibitor. ACS Med. Chem. Lett. 1, 64–69 (2010). source
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In the paper
“over the past 5 years, cysteine-targeted DNA-encoded or protein–nucleic acid-encoded libraries have been used to identify covalent ligands for bromodomains, including PCAF and BRD4, as well as for JNK1, MEK2 and HER2 (refs.160–162).”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Screening platforms
What the sources say
- Not checked yetcites [160] Zimmermann, G. et al. A specific and covalent JNK-1 ligand selected from an encoded self-assembling chemical library. Chem. Eur. J. 23, 8152–8155 (2017). source
- Not checked yetcites [161] Zambaldo, C., Daguer, J.-P., Saarbach, J., Barluenga, S. & Winssinger, N. Screening for covalent inhibitors using DNA-display of small molecule libraries functionalized with cysteine reactive moieties. Med. Chem. Commun. 7, 1340–1351 (2016). source
- Not checked yetcites [162] Daguer, J.-P. et al. Identification of covalent bromodomain binders through DNA display of small molecules. Angew. Chem. Int. Ed. 54, 6057–6061 (2015). source
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In the paper
“Over the past decade, covalent ligand discovery has shifted towards screening more drug-like electrophilic fragments13.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Screening platforms
What the sources say
- Not checked yetcites [13] Lu, W. et al. Fragment-based covalent ligand discovery. RSC Chem. Biol. 2, 354–367 (2021). source
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In the paper
“Overall, covalent docking software provides useful information on ligand–protein interactions when key assumptions can be made — namely, when the reactivity of the electrophile and the site of modification is known.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Screening platforms
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In the paper
“Nevertheless, the success of ketoamide-based NS3/4a inhibitors in increasing the efficacy of interferon–ribavirin therapy emphasizes the utility of the ketoamide group as a serine-reactive electrophile in designing covalent antivirals.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > HCV NS3/4a protease inhibitors
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In the paper
“More recently, even larger covalent DELs (with approximately 100,000,000 members) have been developed and used to identify acrylamide-based and epoxide-based BTK inhibitors with novel scaffolds165.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Screening platforms
What the sources say
- Not checked yetcites [165] Guilinger, J. P. et al. Novel irreversible covalent BTK inhibitors discovered using DNA-encoded chemistry. Bioorg. Med. Chem. 42, 116223 (2021). source
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In the paper
“The epoxyketone moiety in carfilzomib forms a morpholino ring with the catalytic N-terminal threonine of the 20S proteasome”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Covalent proteasome inhibitors
What the sources say
- Not checked yetcites [127] Groll, M., Kim, K. B., Kairies, N., Huber, R. & Crews, C. M. Crystal structure of epoxomicin:20S proteasome reveals a molecular basis for selectivity of α‘,β‘-epoxyketone proteasome inhibitors. J. Am. Chem. Soc. 122, 1237–1238 (2000). source
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In the paper
“However, with an appropriate time-point choice, IC50 values can be a useful tool to rapidly assess potency for covalent inhibitors.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox
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In the paper
“Exchange of the aldehyde electrophile for a boronic acid substantially increased the potency of proteasome inhibition121.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Covalent proteasome inhibitors
What the sources say
- Not checked yetcites [121] Adams, J. et al. Potent and selective inhibitors of the proteasome: dipeptidyl boronic acids. Bioorg. Med. Chem. Lett. 8, 333–338 (1998). source
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In the paper
“Originally, MS-based compound screening grew out of ‘tethering’, which is a technique employed since 2000 that uses libraries of compounds linked to disulfides to identify fragments that bind cysteine-adjacent pockets90,147.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Screening platforms
What the sources say
- Not checked yetcites [90] Erlanson, D. A., Wells, J. A. & Braisted, A. C. Tethering: fragment-based drug discovery. Annu. Rev. Biophys. Biomol. Struct. 33, 199–223 (2004). source
- Not checked yetcites [147] Erlanson, D. A. et al. Site-directed ligand discovery. Proc. Natl Acad. Sci. USA 97, 9367–9372 (2000). source
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In the paper
“More recently, a commercial library of 993 acrylamides and chloroacetamides was screened using intact MS to identify ligands of the deubiquitinase OTUB2 and the pyrophosphatase NUDT7 (ref.156).”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Screening platforms
What the sources say
- Not checked yetcites [156] Resnick, E. et al. Rapid covalent-probe discovery by electrophile-fragment screening. J. Am. Chem. Soc. 141, 8951–8968 (2019). This paper highlights the use of intact MS screening methods paired with structure-guided design to identify covalent fragment ligands against protein targets. source
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In the paper
“However, emerging technologies make it possible to approach covalent ligand discovery from an electrophile-first perspective, in which covalent ligands against protein targets of interest are identified before structure-based optimization.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox
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In the paper
“this proposed mechanism of carfilzomib illustrates how covalency can help to drive selectivity through highly specific mechanisms.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Covalent proteasome inhibitors
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In the paper
“An aldehyde-containing natural product and several synthetic aldehyde analogues were found to prevent polymerization by increasing the affinity of HbS for oxygen143.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Mutant-haemoglobin modulators
What the sources say
- Not checked yetcites [143] Metcalf, B. et al. Discovery of GBT440, an orally bioavailable r-state stabilizer of sickle cell hemoglobin. ACS Med. Chem. Lett. 8, 321–326 (2017). source
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In the paper
“Chemoproteomic platforms enable the identification of covalent compounds and their corresponding ligandable sites on target proteins directly in complex biological systems.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
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In the paper
“The reversibility of the serine–boron bond hinders chemoproteomic profiling experiments commonly used to characterize the selectivity of covalent ligands.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Other boron-containing drugs
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In the paper
“The success of voxelotor is similar to that of ibrutinib in demonstrating that covalent drugs can be dosed at high amounts given favourable absorption, distribution, metabolism and excretion (ADME) properties.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Mutant-haemoglobin modulators
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In the paper
“The effect of bortezomib comes from the boronic acid covalently binding to the hydroxy group of the β5 subunit N-terminal threonine of the 20S proteasome, leading to inhibition of the proteasome’s chymotrypsin-like activity125.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Covalent proteasome inhibitors
What the sources say
- Not checked yetcites [125] Cromm, P. M. & Crews, C. M. The proteasome in modern drug discovery: second life of a highly valuable drug target. ACS Cent. Sci. 3, 830–838 (2017). source
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In the paper
“ABPP facilitates the discovery of covalently ligandable sites and the corresponding ligands in complex biological samples.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
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In the paper
“Most computational programs for covalent docking rely on directly linking models to model conformations under the constraint of a predefined bond between a ligand and a corresponding amino acid site.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Screening platforms
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In the paper
“Furthermore, the discovery of voxelotor shows how the identification of unusually reactive amino acid residues, such as the α-haemoglobin N-terminus, provides opportunities for drug discovery.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Mutant-haemoglobin modulators
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In the paper
“A library of 3,300 acrylamides was screened in three assays: a thiol reactivity assay, a RAF-coupled nucleotide exchange assay and an intact MS assay158.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Screening platforms
What the sources say
- Not checked yetcites [158] Shin, Y. et al. Discovery of N-(1-acryloylazetidin-3-yl)-2-(1H-indol-1-yl)acetamides as covalent inhibitors of KRASG12C. ACS Med. Chem. Lett. 10, 1302–1308 (2019). This study details the discovery of covalent KRAS(G12C) inhibitors through screening an acrylamide library, which laid the groundwork for the discovery of sotorasib. source
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In the paper
“This covalent interaction is relatively reversible owing to elimination of the serine alcohol group from the protein–inhibitor adduct114.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > HCV NS3/4a protease inhibitors
What the sources say
- Not checked yetcites [114] McCauley, J. A. & Rudd, M. T. Hepatitis C virus NS3/4a protease inhibitors. Curr. Opin. Pharmacol. 30, 84–92 (2016). source
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In the paper
“DOCKovalent uses non-covalent docking methods to pre-generate conformations and states for an electrophilic virtual library and then samples each state against the target nucleophile.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Screening platforms
What the sources say
- Not checked yetcites [169] London, N. et al. Covalent docking of large libraries for the discovery of chemical probes. Nat. Chem. Biol. 10, 1066–1072 (2014). source
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In the paper
“To ensure that potent covalent inhibitors are not promiscuous ligands that lack selectivity, electrophilic compounds are frequently tested for reactivity, usually with respect to thiols.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox
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In the paper
“Several additional boron-containing drugs inhibit serine hydrolases beyond the proteasome through formation of covalent adducts between catalytic serine residues and boron133,134.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Other boron-containing drugs
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“cysteine reactivity and ligandable sites were mapped in mutant Kelch-like ECH-associated protein 1 (KEAP1) and compared with those in wild-type KEAP1 NSCLC lines.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [181] Bar-Peled, L. et al. Chemical proteomics identifies druggable vulnerabilities in a genetically defined cancer. Cell 171, 696–709.e23 (2017). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Beyond degradation, the identification of non-inhibitory covalent ligands has the potential to contribute to the discovery of novel induced proximity modalities.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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In the paper
“The covalent ligands discovered with this approach and their corresponding ligandable sites were used to help elucidate the role of caspase 8 and caspase 10 in extrinsic apoptosis in T cells”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [180] Backus, K. M. et al. Proteome-wide covalent ligand discovery in native biological systems. Nature 534, 570–574 (2016). This work demonstrates how chemoproteomics can be paired with covalent ligand screening to identify the protein targets of covalent ligands in complex biological samples. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The use of competitive isoTOP-ABPP was expanded to identify proteome-wide targets of a small covalent fragment library by competing individual acrylamide and chloroacetamide fragments against an iodoacetamide–alkyne probe180.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [180] Backus, K. M. et al. Proteome-wide covalent ligand discovery in native biological systems. Nature 534, 570–574 (2016). This work demonstrates how chemoproteomics can be paired with covalent ligand screening to identify the protein targets of covalent ligands in complex biological samples. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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In the paper
“Using this approach, it was discovered that the hyper-reactivity of cysteines predicts their functionality in catalysis and at sites of post-translational modifications177.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [177] Weerapana, E. et al. Quantitative reactivity profiling predicts functional cysteines in proteomes. Nature 468, 790–795 (2010). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“In the first reports of the isoTOP-ABPP (isotopic tandem orthogonal proteolysis–activity-based protein profiling) approach, an iodoacetamide probe functionalized with an alkyne handle was used to identify hyper-reactive cysteines across the proteome176,177”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [176] Weerapana, E., Speers, A. E. & Cravatt, B. F. Tandem orthogonal proteolysis-activity-based protein profiling (TOP-ABPP) — a general method for mapping sites of probe modification in proteomes. Nat. Protoc. 2, 1414–1425 (2007). source
- Not checked yetcites [177] Weerapana, E. et al. Quantitative reactivity profiling predicts functional cysteines in proteomes. Nature 468, 790–795 (2010). source
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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None of the sources cited for this claim have been checked yet.
In the paper
“Since 2019, covalent recruiters have been used to validate a large proportion of the E3 ligases that have been harnessed for targeted protein degradation, including RING finger protein 114 (RNF114), RNF4, DDB1 and CUL4-associated factor 16 (DCAF16), DCAF11, KEAP1 and, most recently, fem-1 homologue B (FEM1B)187–193.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [187] Spradlin, J. N. et al. Harnessing the anti-cancer natural product nimbolide for targeted protein degradation. Nat. Chem. Biol. 15, 747–755 (2019). source
- Not checked yetcites [188] Luo, M. et al. Chemoproteomics-enabled discovery of covalent RNF114-based degraders that mimic natural product function. Cell Chem. Biol. 28, 559–566.e15 (2021). source
- Not checked yetcites [189] Ward, C. C. et al. Covalent ligand screening uncovers a RNF4 E3 ligase recruiter for targeted protein degradation applications. ACS Chem. Biol. 14, 2430–2440 (2019). source
- Not checked yetcites [190] Zhang, X., Crowley, V. M., Wucherpfennig, T. G., Dix, M. M. & Cravatt, B. F. Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16. Nat. Chem. Biol. 15, 737–746 (2019). source
- Not checked yetcites [191] Zhang, X. et al. DCAF11 supports targeted protein degradation by electrophilic proteolysis-targeting chimeras. J. Am. Chem. Soc. 143, 5141–5149 (2021). source
- Not checked yetcites [192] Tong, B. et al. Bardoxolone conjugation enables targeted protein degradation of BRD4. Sci. Rep. 10, 15543 (2020).
- Not checked yetcites [193] Henning, N. J. et al. Discovery of a covalent FEM1B recruiter for targeted protein degradation applications. J. Am. Chem. Soc. 44, 701–708 (2022). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Most bifunctional degraders recruit CRBN or VHL, but there are more than 600 E3 ligases with varying substrate scopes.
In the paper
“this approach was also used to identify several proteins that could be targeted covalently to impair T cell activity, including BIRC2 and BIRC3, the nucleosome remodelling deacetylase (NuRD) complex, and the kinases ITK and CYTIP.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [182] Vinogradova, E. V. et al. An activity-guided map of electrophile-cysteine interactions in primary human T cells. Cell 182, 1009–1026.e29 (2020). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“On the basis of analyses of chemoproteomic data sets assessing cysteine reactivity, 97% of E3 ligases possess reactive cysteines”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [194] Belcher, B. P., Ward, C. C. & Nomura, D. K. Ligandability of E3 ligases for targeted protein degradation applications. Biochemistry https://doi.org/10.1021/acs.biochem.1c00464 (2021). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Most bifunctional degraders recruit CRBN or VHL, but there are more than 600 E3 ligases with varying substrate scopes.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In general, the identification of non-inhibitory, allosteric ligands through covalent ligand screening has the potential to facilitate recruitment of other enzymes (such as kinases and deacetylases) to target proteins and direct protein function to neosubstrates for therapeutic benefit.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“showing that this approach can rapidly identify compounds that target proteins of biological interest.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [180] Backus, K. M. et al. Proteome-wide covalent ligand discovery in native biological systems. Nature 534, 570–574 (2016). This work demonstrates how chemoproteomics can be paired with covalent ligand screening to identify the protein targets of covalent ligands in complex biological samples. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“disrupting the IRAK4–MYD88 interaction suppressed the production of interferon-α in plasmacytoid dendritic cells184,185.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [185] Zaro, B. W. et al. Dimethyl fumarate disrupts human innate immune signaling by targeting the IRAK4–MyD88 complex. J. Immunol. 202, 2737–2746 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“ABPP was paired with a MYC transcription factor activity assay to identify a covalent MYC ligand, EN4 (ref.179).”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [179] Boike, L. et al. Discovery of a functional covalent ligand targeting an intrinsically disordered cysteine within MYC. Cell Chem. Biol. 28, 4–13 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Although dimethyl fumarate has been used for three decades to treat psoriasis and was approved by the FDA in 2013 for the treatment of multiple sclerosis, the direct covalent targets of dimethyl fumarate remained unclear until more recently.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [184] Blewett, M. M. et al. Chemical proteomic map of dimethyl fumarate–sensitive cysteines in primary human T cells. Sci. Signal. 9, rs10 (2016). source
- Not checked yetcites [185] Zaro, B. W. et al. Dimethyl fumarate disrupts human innate immune signaling by targeting the IRAK4–MyD88 complex. J. Immunol. 202, 2737–2746 (2019). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Several hydrazine-containing compounds act as mechanism-based inhibitors of monoamine oxidase (MAO) A and B, whereby activation by MAO enables alkylation of a flavin cofactor, inhibiting the enzyme196.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Nucleophilic covalent ligands
What the sources say
- Not checked yetcites [196] Binda, C. et al. Structural and mechanistic studies of arylalkylhydrazine inhibition of human monoamine oxidases A and B. Biochemistry 47, 5616–5625 (2008). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“SLC-ABPP was used to analyse spleen tissue extracted from C57BL/6 mice treated with ibrutinib183.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [183] Kuljanin, M. et al. Reimagining high-throughput profiling of reactive cysteines for cell-based screening of large electrophile libraries. Nat. Biotechnol. 39, 630–641 (2021). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Disrupting the interaction of PKCθ with the costimulatory receptor CD28 reduced T cell activation”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [184] Blewett, M. M. et al. Chemical proteomic map of dimethyl fumarate–sensitive cysteines in primary human T cells. Sci. Signal. 9, rs10 (2016). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The authors discovered compounds that bind to a ligandable cysteine on the nuclear receptor NR0B1, which is regulated by NRF2, a substrate of KEAP1 (ref.181).”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [181] Bar-Peled, L. et al. Chemical proteomics identifies druggable vulnerabilities in a genetically defined cancer. Cell 171, 696–709.e23 (2017). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“In separate studies, chemoproteomic approaches were used to identify protein kinase Cθ (PKCθ) and IRAK4 as targets of dimethyl fumarate184,185.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [184] Blewett, M. M. et al. Chemical proteomic map of dimethyl fumarate–sensitive cysteines in primary human T cells. Sci. Signal. 9, rs10 (2016). source
- Not checked yetcites [185] Zaro, B. W. et al. Dimethyl fumarate disrupts human innate immune signaling by targeting the IRAK4–MyD88 complex. J. Immunol. 202, 2737–2746 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“When paired with a parallel phenotypic screen against a desired outcome (such as cancer cell death), this methodology facilitates the identification of functional covalent ligands and their corresponding protein targets in a high-throughput manner.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“suggesting that covalent approaches to harness more E3 ligases could continue to be successful194.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [194] Belcher, B. P., Ward, C. C. & Nomura, D. K. Ligandability of E3 ligases for targeted protein degradation applications. Biochemistry https://doi.org/10.1021/acs.biochem.1c00464 (2021). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Most bifunctional degraders recruit CRBN or VHL, but there are more than 600 E3 ligases with varying substrate scopes.
In the paper
“Instead of focusing on active sites, more recent ABPP approaches use MS and broadly reactive chemical probes to also map allosteric sites176.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [176] Weerapana, E., Speers, A. E. & Cravatt, B. F. Tandem orthogonal proteolysis-activity-based protein profiling (TOP-ABPP) — a general method for mapping sites of probe modification in proteomes. Nat. Protoc. 2, 1414–1425 (2007). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“IsoTOP-ABPP can also be used to identify the protein targets of known electrophilic drugs.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Covalent drug discovery platforms have facilitated the expansion of targeted protein degradation approaches by enabling the discovery of covalent recruiters against E3 ubiquitin ligases14,187–193.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [14] Spradlin, J. N., Zhang, E. & Nomura, D. K. Reimagining druggability using chemoproteomic platforms. Acc. Chem. Res. 54, 1801–1813 (2021). source
- Not checked yetcites [187] Spradlin, J. N. et al. Harnessing the anti-cancer natural product nimbolide for targeted protein degradation. Nat. Chem. Biol. 15, 747–755 (2019). source
- Not checked yetcites [188] Luo, M. et al. Chemoproteomics-enabled discovery of covalent RNF114-based degraders that mimic natural product function. Cell Chem. Biol. 28, 559–566.e15 (2021). source
- Not checked yetcites [189] Ward, C. C. et al. Covalent ligand screening uncovers a RNF4 E3 ligase recruiter for targeted protein degradation applications. ACS Chem. Biol. 14, 2430–2440 (2019). source
- Not checked yetcites [190] Zhang, X., Crowley, V. M., Wucherpfennig, T. G., Dix, M. M. & Cravatt, B. F. Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16. Nat. Chem. Biol. 15, 737–746 (2019). source
- Not checked yetcites [191] Zhang, X. et al. DCAF11 supports targeted protein degradation by electrophilic proteolysis-targeting chimeras. J. Am. Chem. Soc. 143, 5141–5149 (2021). source
- Not checked yetcites [192] Tong, B. et al. Bardoxolone conjugation enables targeted protein degradation of BRD4. Sci. Rep. 10, 15543 (2020).
- Not checked yetcites [193] Henning, N. J. et al. Discovery of a covalent FEM1B recruiter for targeted protein degradation applications. J. Am. Chem. Soc. 44, 701–708 (2022). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Most bifunctional degraders recruit CRBN or VHL, but there are more than 600 E3 ligases with varying substrate scopes.
In the paper
“a targeted protein stabilization platform, termed deubiquitinase-targeting chimeras (DUBTACs) has been developed using a covalent deubiquitinase recruiter195.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [195] Henning, N. J. et al. Deubiquitinase-targeting chimeras for targeted protein stabilization. Nat. Chem. Biol. 18, 412–421 (2022). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Through analysis of chemoproteomic data and an ABPP-based screen, a covalent OTUB1 recruiter was discovered that could be incorporated into bifunctional compounds that stabilize mutant cystic fibrosis transmembrane conductance regulator (CFTR), the degradation of which drives cystic fibrosis.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [195] Henning, N. J. et al. Deubiquitinase-targeting chimeras for targeted protein stabilization. Nat. Chem. Biol. 18, 412–421 (2022). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Cysteine ligandability has also been explored in activated T cells through the use of promiscuous fragment-like compounds, termed ‘scout fragments’, to map ligandability and functional assays to identify more structurally complex electrophilic compounds that suppress T cell activity182.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [182] Vinogradova, E. V. et al. An activity-guided map of electrophile-cysteine interactions in primary human T cells. Cell 182, 1009–1026.e29 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“a multiplexed in vivo screening platform was developed in which barcoded pancreatic ductal adenocarcinoma lines were pretreated with electrophilic compounds and injected into mice to observe the compound-dependent decrease in metastatic potential186.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [186] Grüner, B. M. et al. An in vivo multiplexed small-molecule screening platform. Nat. Methods 13, 883–889 (2016). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Hydrazine-based probes have also been used to help identify and characterize ligands for proteins with electrophilic cofactors or post-translational modifications198,199.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Nucleophilic covalent ligands
What the sources say
- Not checked yetcites [198] Wang, X. et al. Discovery of potent and selective inhibitors against protein-derived electrophilic cofactors. J. Am. Chem. Soc. 144, 5377–5388 (2022). source
- Not checked yetcites [199] Lin, Z. et al. Activity-based hydrazine probes for protein profiling of electrophilic functionality in therapeutic targets. ACS Cent. Sci. 7, 1524–1534 (2021). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“IsoTOP-ABPP experiments using several lysine-directed probes have proved powerful in profiling lysine reactivity across the proteome200,201.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Lysine-directed covalent ligands
What the sources say
- Not checked yetcites [200] Hacker, S. M. et al. Global profiling of lysine reactivity and ligandability in the human proteome. Nat. Chem. 9, 1181–1190 (2017). source
- Not checked yetcites [201] Ward, C. C., Kleinman, J. I. & Nomura, D. K. NHS-esters as versatile reactivity-based probes for mapping proteome-wide ligandable hotspots. ACS Chem. Biol. 12, 1478–1483 (2017). source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Cysteine's low abundance provides selectivity but restricts opportunities to covalently target specific proteins.
- Rests on an assumption: The ε-amino group of lysine is not nucleophilic enough under physiological conditions, so efficient lysine-targeting covalent ligands require unusually reactive lysines.
In the paper
“A sulfonyl fluoride-bearing promiscuous kinase inhibitor that targets a conserved lysine in the ATP-binding site was also used as a probe to profile kinase inhibitor selectivity in live cells208.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Lysine-directed covalent ligands
What the sources say
- Not checked yetcites [208] Zhao, Q. et al. Broad-spectrum kinase profiling in live cells with lysine-targeted sulfonyl fluoride probes. J. Am. Chem. Soc. 139, 680–685 (2017). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Cysteine's low abundance provides selectivity but restricts opportunities to covalently target specific proteins.
- Rests on an assumption: The ε-amino group of lysine is not nucleophilic enough under physiological conditions, so efficient lysine-targeting covalent ligands require unusually reactive lysines.
In the paper
“ABPP principles and ‘reverse-polarity’ probes have been employed to study electrophilic post-translational modifications, such as N-terminal pyruvoyl and glyoxylyl modifications, that can react with hydrazine-containing compounds197.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Nucleophilic covalent ligands
What the sources say
- Not checked yetcites [197] Matthews, M. L. et al. Chemoproteomic profiling and discovery of protein electrophiles in human cells. Nat. Chem. 9, 234–243 (2017). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“A recent preprint reported the use of a chemoproteomic approach to profile the amino acid reactivity preference of 54 different electrophiles, which will prove to be a great resource for covalent ligand discovery210.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Lysine-directed covalent ligands
What the sources say
- Not checked yetcites [210] Zanon, P. R. A. et al. Profiling the proteome-wide selectivity of diverse electrophiles. ChemRxiv https://doi.org/10.26434/chemrxiv.14186561.v1 (2021). source
plain- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: Cysteine's low abundance provides selectivity but restricts opportunities to covalently target specific proteins.
- Rests on an assumption: The ε-amino group of lysine is not nucleophilic enough under physiological conditions, so efficient lysine-targeting covalent ligands require unusually reactive lysines.
- It may state two separate claims as one. 67
- Probably not a substantial claim. 21
Every source the paper cites for this claim was checked and supports it.
In the paper
“Wild-type KRAS is carefully regulated between the active GTP-bound state and inactive GDP-bound state, but many KRAS mutations attenuate GTPase activity, leading to low rates of GTP hydrolysis and elevated RAS signalling, driving tumorigenesis87.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Covalent KRAS(G12C) inhibitors
What the sources say
- Supportedcites [87] Janes, M. R. et al. Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor. Cell 172, 578–589.e17 (2018). source
The Introduction (page not provided) says that a KRAS codon 12 mutation attenuates GTPase activity, causing activated GTP-bound KRAS to accumulate and downstream signalling pathways to activate. The Discussion (page not provided) describes mutant KRAS as a driver of tumorigenesis. Together, these passages support the attributed mechanism, although the paper discusses codon 12 mutations specifically. (LLM, conf=0.88)
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In the paper
“Osimertinib was granted accelerated approval by the FDA in 2015 as a second-line treatment for NSCLC, and was approved as a first-line treatment for metastatic NSCLC in 2018 (ref.49).”
§ Advances in covalent drug discovery > Discoveries by ligand-first approaches > Covalent EGFR inhibitors
What the sources say
- Not checked yetcites [49] Mok, T. S. et al. Osimertinib or platinum–pemetrexed in EGFR T790M–positive lung cancer. N. Engl. J. Med. 376, 629–640 (2016). source
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Many early covalent drugs were discovered serendipitously and bind active sites to inhibit enzymatic activity4.”
§ Advances in covalent drug discovery > Introduction
What the sources say
- Not checked yetcites [4] De Cesco, S., Kurian, J., Dufresne, C., Mittermaier, A. K. & Moitessier, N. Covalent inhibitors design and discovery. Eur. J. Med. Chem. 138, 96–114 (2017). source
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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In the paper
“However, osimertinib depends on Cys797 for covalent binding, and C797X mutations account for 15% of cases of resistance to second-line osimertinib50–52.”
§ Advances in covalent drug discovery > Discoveries by ligand-first approaches > Covalent EGFR inhibitors
What the sources say
- Not checked yetcites [50] Passaro, A., Jänne, P. A., Mok, T. & Peters, S. Overcoming therapy resistance in EGFR-mutant lung cancer. Nat. Cancer 2, 377–391 (2021). source
- Not checked yetcites [51] Leonetti, A. et al. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br. J. Cancer 121, 725–737 (2019). source
- Not checked yetcites [52] Thress, K. S. et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non–small cell lung cancer harboring EGFR T790M. Nat. Med. 21, 560–562 (2015). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Aspirin’s mechanism of action was unknown until 1971, when it was discovered to exert its anti-inflammatory effects by acetylating Ser529 in the substrate-binding channel of cyclooxygenase 1, preventing conversion of the substrate arachidonic acid into prostaglandins20.”
§ Advances in covalent drug discovery > History of covalent drugs
What the sources say
- Not checked yetcites [20] Vane, J. R. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature 231, 232–235 (1971).
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“β-Lactam antibiotics such as penicillin (Fig. 1), produced by Penicillium fungi, bind to penicillin-binding proteins (PBPs), which are involved in bacterial cell wall synthesis21.”
- Also stated in: § History of covalent drugs · plain
“All PBPs contain active-site serine residues that can be acylated by penicillin, inhibiting PBP activity and leading to cell membrane rupture21.”
§ Advances in covalent drug discovery > History of covalent drugs
What the sources say
- Not checked yetcites [21] Nicola, G., Tomberg, J., Pratt, R. F., Nicholas, R. A. & Davies, C. Crystal structures of covalent complexes of β-lactam antibiotics with Escherichia coli penicillin-binding protein 5: toward an understanding of antibiotic specificity. Biochemistry 49, 8094–8104 (2010). source
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- Also stated in: § History of covalent drugs · plain
In the paper
“Covalent drugs incorporate a mildly reactive functional group that forms a covalent bond with protein targets to confer additional affinity beyond the non-covalent interactions involved in drug binding1.”
§ Advances in covalent drug discovery > Introduction
What the sources say
- Not checked yetcites [1] Tuley, A. & Fast, W. The taxonomy of covalent inhibitors. Biochemistry 57, 3326–3337 (2018). This review summarizes the mechanisms of covalent inhibition of enzymes and comprehensively covers examples for each mechanism. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Bortezomib (Fig. 1), a dipeptide boronic acid that covalently binds to and inhibits a catalytic threonine residue of the 26S proteasome, was approved by the FDA in 2003 to treat patients with multiple myeloma30.”
§ Advances in covalent drug discovery > History of covalent drugs
What the sources say
- Not checked yetcites [30] Curran, M. P. & McKeage, K. Bortezomib: a review of its use in patients with multiple myeloma. Drugs 69, 859–888 (2009). source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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In the paper
“Over the past 30 years, the rational design of covalent drugs has garnered increased interest, and covalently targeting non-conserved amino acids to increase selectivity has become commonplace2,5.”
§ Advances in covalent drug discovery > Introduction
What the sources say
- Not checked yetcites [2] Singh, J., Petter, R. C., Baillie, T. A. & Whitty, A. The resurgence of covalent drugs. Nat. Rev. Drug Discov. 10, 307–317 (2011). This review illustrates the key features of covalent drug discovery with emphasis on targeted covalent inhibitors. source
- Not checked yetcites [5] Sutanto, F., Konstantinidou, M. & Dömling, A. Covalent inhibitors: a rational approach to drug discovery. RSC Med. Chem. 11, 876–884 (2020). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Moreover, potent inhibition through covalent modification has enabled targeting of traditionally ‘undruggable’ proteins, exemplified by the approval of sotorasib (Amgen), which is an inhibitor of mutant KRAS(G12C), a GTPase that resisted decades of drug discovery efforts9,10”
§ Advances in covalent drug discovery > Introduction
What the sources say
- Not checked yetcites [9] Moore, A. R., Rosenberg, S. C., McCormick, F. & Malek, S. RAS-targeted therapies: is the undruggable drugged? Nat. Rev. Drug Discov. 19, 533–552 (2020). source
- Not checked yetcites [10] Huang, L., Guo, Z., Wang, F. & Fu, L. KRAS mutation: from undruggable to druggable in cancer. Signal Transduct. Target. Ther. 6, 386 (2021). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Cys797 is located adjacent to the ATP-binding site, and irreversible binding of EGFR ligands to EGFR partially restores activity against the T790M gatekeeper mutant33.”
§ Advances in covalent drug discovery > Discoveries by ligand-first approaches > Covalent EGFR inhibitors
What the sources say
- Not checked yetcites [33] Ou, S.-H. I. Second-generation irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs): a better mousetrap? A review of the clinical evidence. Crit. Rev. Oncol. Hematol. 83, 407–421 (2012). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“A third generation of EGFR inhibitors followed afatinib; these covalent inhibitors selectively target the T790M mutant over wild-type EGFR, and include WZ4002 (Dana–Farber Cancer Institute)43, osimertinib44,45 and rociletinib (Clovis Oncology; CO-1686)46 (Fig. 2c).”
§ Advances in covalent drug discovery > Discoveries by ligand-first approaches > Covalent EGFR inhibitors
What the sources say
- Not checked yetcites [43] Zhou, W. et al. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature 462, 1070–1074 (2009). This paper reports the discovery of covalent EGFR inhibitors selective for the T790M gatekeeper mutation. source
- Not checked yetcites [44] Cross, D. A. E. et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 4, 1046–1061 (2014). source
- Not checked yetcites [45] Finlay, M. R. V. et al. Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. J. Med. Chem. 57, 8249–8267 (2014). source
- Not checked yetcites [46] Walter, A. O. et al. Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. Cancer Discov. 3, 1404–1415 (2013). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Overactivity of the receptor tyrosine kinase EGFR drives the progression of non-small-cell lung cancer (NSCLC), making EGFR a key drug target in oncology31.”
§ Advances in covalent drug discovery > Discoveries by ligand-first approaches > Covalent EGFR inhibitors
What the sources say
- Not checked yetcites [31] Lynch, T. J., Okimoto, R. A., Supko, J. G. & Settleman, J. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non–small-cell lung cancer to gefitinib. N. Engl. J. Med. 350, 2129–2139 (2004). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Another covalent antibiotic is the epoxide-containing fosfomycin (Fig. 1), which is produced by some Streptomyces bacteria and acts by reacting with the catalytic cysteine of UDP-N-acetylglucosamine-enolpyruvyl transferase (MurA) to disrupt peptidoglycan synthesis and induce membrane rupture22–24.”
§ Advances in covalent drug discovery > History of covalent drugs
What the sources say
- Not checked yetcites [22] Dijkmans, A. C. et al. Fosfomycin: pharmacological, clinical and future perspectives. Antibiotics 6, 24 (2017). source
- Not checked yetcites [23] Hendlin, D. et al. Phosphonomycin, a new antibiotic produced by strains of Streptomyces. Science 166, 122–123 (1969). source
- Not checked yetcites [24] Kahan, F. M., Kahan, J. S., Cassidy, P. J. & Kropp, H. The mechanism of action of fosfomycin (phosphonomycin). Ann. NY Acad. Sci. 235, 364–386 (1974). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“more traditional covalent targeting of protease active sites has continued to yield valuable drugs, such as nirmatrelvir (Pfizer), which inhibits the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro)11”
§ Advances in covalent drug discovery > Introduction
What the sources say
- Not checked yetcites [11] Vandyck, K. & Deval, J. Considerations for the discovery and development of 3-chymotrypsin-like cysteine protease inhibitors targeting SARS-CoV-2 infection. Curr. Opin. Virol. 49, 36–40 (2021). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“include the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib (AbbVie) and the epidermal growth factor receptor (EGFR) inhibitor osimertinib (AstraZeneca), with sales totalling US$8.43 billion and $4.33 billion in 2020, respectively7,8.”
§ Advances in covalent drug discovery > Introduction
What the sources say
- Not checked yetcites [7] Lonsdale, R. & Ward, R. A. Structure-based design of targeted covalent inhibitors. Chem. Soc. Rev. 47, 3816–3830 (2018). source
- Not checked yetcites [8] Sagonowsky, E. The top 20 drugs by worldwide sales in 2020. Fierce Pharma https://www.fiercepharma.com/special-report/top-20-drugs-by-2020-sales (2021).
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“This mutation of the gatekeeper residue in the ATP-binding site of EGFR not only decreases the binding affinity of many reversible inhibitors for EGFR but also increases the binding affinity of EGFR for ATP36.”
§ Advances in covalent drug discovery > Discoveries by ligand-first approaches > Covalent EGFR inhibitors
What the sources say
- Not checked yetcites [36] Yun, C.-H. et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc. Natl Acad. Sci. USA 105, 2070–2075 (2008). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“KRAS is a GTPase-encoding oncogene that is mutated in about 25% of all cancers, most notably in pancreatic, colorectal and lung cancers86.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Covalent KRAS(G12C) inhibitors
What the sources say
- Not checked yetcites [86] Goebel, L., Müller, M. P., Goody, R. S. & Rauh, D. KRasG12C inhibitors in clinical trials: a short historical perspective. RSC Med. Chem. 11, 760–770 (2020). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“displayed potent inhibition in a FRET-based assay across all human coronaviruses, while no inhibitory effects were seen against human cysteine or serine proteases.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > SARS-CoV-2 main protease inhibitors
What the sources say
- Not checked yetcites [103] Owen, D. R. et al. An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19. Science 374, 1586–1593 (2021). This work describes the discovery of PF-07321332, later named nirmatrelvir, an orally bioavailable SARS-CoV-2 Mpro inhibitor. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In 2016, Wellspring Biosciences disclosed ARS-853, which is a selective covalent inhibitor of KRAS(G12C) with in cellulo efficacy in the low micromolar range92.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Covalent KRAS(G12C) inhibitors
What the sources say
- Not checked yetcites [92] Patricelli, M. P. et al. Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state. Cancer Discov. 6, 316–329 (2016). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“ARS-853 treatment in KRAS(G12C)-dependent cell lines decreased the amount of active KRAS(G12C), inhibited downstream RAS signalling and induced apoptosis92.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Covalent KRAS(G12C) inhibitors
What the sources say
- Not checked yetcites [92] Patricelli, M. P. et al. Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state. Cancer Discov. 6, 316–329 (2016). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Binding of compound 12 to the switch II pocket impaired KRAS signalling by shifting nucleotide affinity from favouring GTP to GDP and led to the accumulation of KRAS in its inactive state91.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Covalent KRAS(G12C) inhibitors
What the sources say
- Not checked yetcites [91] Lito, P., Solomon, M., Li, L.-S., Hansen, R. & Rosen, N. Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. Science 351, 604–608 (2016). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Several covalent inhibitors of fibroblast growth factor receptor 4 (FGFR4) target the non-conserved Cys552 residue in FGFR4 to confer selectivity over FGFR1, FGFR2 and FGFR3, as well as to overcome mutations that confer resistance to reversible FGFR inhibitors in hepatocellular carcinoma (HCC)83,84.”
§ Advances in covalent drug discovery > Discoveries by ligand-first approaches > Other covalent kinase inhibitors
What the sources say
- Not checked yetcites [83] Kim, R. D. et al. First-in-human phase I study of fisogatinib (BLU-554) validates aberrant FGF19 signaling as a driver event in hepatocellular carcinoma. Cancer Discov. 9, 1696–1707 (2019). source
- Not checked yetcites [84] Tan, L. et al. Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors. Proc. Natl Acad. Sci. USA 111, E4869–E4877 (2014).
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Both JAK3 and mutant EGFR(T790M) contain a methionine gatekeeper, as well as a homologous cysteine adjacent to the ATP-binding site.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > SARS-CoV-2 main protease inhibitors
What the sources say
- Not checked yetcites [79] Tan, L. et al. Development of selective covalent Janus kinase 3 inhibitors. J. Med. Chem. 58, 6589–6606 (2015). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“In December 2021, the FDA issued an Emergency Use Authorization for Pfizer’s Paxlovid (a combination of nirmatrelvir and ritonavir) to treat mild-to-moderate COVID-19 (caused by SARS-CoV-2) in adults and some paediatric patients, marking the first approved oral treatment for the disease99.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > SARS-CoV-2 main protease inhibitors
What the sources say
- Not checked yetcites [99] US FDA. Coronavirus (COVID-19) Update: FDA Authorizes First Oral Antiviral for Treatment of COVID-19. FDA https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19 (2021).
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“KRAS does not have accessible pockets for reversible inhibitors to bind to, competitive inhibitors would need to overcome the picomolar binding affinities of GTP and GDP, and inhibitors active against wild-type KRAS could show on-target toxicity86,88.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Covalent KRAS(G12C) inhibitors
What the sources say
- Not checked yetcites [86] Goebel, L., Müller, M. P., Goody, R. S. & Rauh, D. KRasG12C inhibitors in clinical trials: a short historical perspective. RSC Med. Chem. 11, 760–770 (2020). source
- Not checked yetcites [88] Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A. & Shokat, K. M. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503, 548–551 (2013). This work showcases the use of tethering as a screening methodology for discovering covalent ligands against KRAS(G12C) and further identifies ligands against this oncogenic protein. source
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“SARS-CoV-2 Mpro shares 96% sequence identity with SARS-CoV-1 Mpro, and there is 100% sequence overlap of the catalytic sites102.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > SARS-CoV-2 main protease inhibitors
What the sources say
- Not checked yetcites [102] Hoffman, R. L. et al. Discovery of ketone-based covalent inhibitors of coronavirus 3CL proteases for the potential therapeutic treatment of COVID-19. J. Med. Chem. 63, 12725–12747 (2020). source
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Overcoming historical concerns relating to the potential toxicity of covalent drugs, the success of ibrutinib demonstrates that rationally designed covalent drugs can achieve acceptable safety profiles and blockbuster status.”
§ Advances in covalent drug discovery > Discoveries by ligand-first approaches > Covalent BTK inhibitors
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“activity in antiviral cell-based assays, stability in plasma and low clearance in vivo103.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > SARS-CoV-2 main protease inhibitors
What the sources say
- Not checked yetcites [103] Owen, D. R. et al. An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19. Science 374, 1586–1593 (2021). This work describes the discovery of PF-07321332, later named nirmatrelvir, an orally bioavailable SARS-CoV-2 Mpro inhibitor. source
boosted- Asserted: passes — The authors put it forward as true.
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In the paper
“Most prominent among these is acalabrutinib (AstraZeneca), approved by the FDA in 2019 to treat CLL, which contains a butyramide electrophile instead of an acrylamide69.”
- Also stated in: § Covalent BTK inhibitors · hedged
“The butyramide electrophile is less reactive than an acrylamide, which, in addition to other substitutions, is hypothesized to account for the superior selectivity of acalabrutinib compared with ibrutinib for BTK and could be responsible for the reduced number of adverse cardiovascular events70,71.”
§ Advances in covalent drug discovery > Discoveries by ligand-first approaches > Covalent BTK inhibitors
What the sources say
- Not checked yetcites [69] Barf, T. et al. Acalabrutinib (ACP-196): a covalent Bruton tyrosine kinase inhibitor with a differentiated selectivity and in vivo potency profile. J. Pharmacol. Exp. Ther. 363, 240–252 (2017). source
- Not checked yetcites [70] Byrd, J. C. et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 374, 323–332 (2016). source
- Not checked yetcites [71] Byrd, J. C. et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J. Clin. Oncol. 39, 3441–3452 (2021). source
plainconditional- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Covalent BTK inhibitors · hedged
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In the paper
“Sotorasib (AMG-510) (Table 1) was the first selective KRAS(G12C) inhibitor to enter clinical trials in 2018 and was developed by Amgen, building on discoveries from a partnership with Carmot Therapeutics in which a custom library of small molecules that covalently bind cysteine were screened against KRAS(G12C)93.”
- Also stated in: § Covalent KRAS(G12C) inhibitors · plain
“A phase II clinical trial investigating sotorasib was successfully completed in 2020, and was followed by FDA approval for the treatment of adults with KRASG12C-mutated locally advanced or metastatic NSCLC in May 2021 (ref.95).”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Covalent KRAS(G12C) inhibitors
What the sources say
plain- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Covalent KRAS(G12C) inhibitors · plain
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The success of covalent KRAS(G12C) inhibitors validates an electrophile-first approach to covalent drug discovery and affirms the importance of covalent fragment screening techniques (discussed below).”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Covalent KRAS(G12C) inhibitors
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Similarly to EGFR inhibitors, ibrutinib binds to a cysteine residue (Cys481) adjacent to the ATP-binding site in BTK, and because only a few kinases have a homologous cysteine, ibrutinib should exhibit a degree of selectivity for BTK over other kinases64.”
§ Advances in covalent drug discovery > Discoveries by ligand-first approaches > Covalent BTK inhibitors
What the sources say
- Not checked yetcites [64] Davids, M. S. & Brown, J. R. Ibrutinib: a first in class covalent inhibitor of Bruton’s tyrosine kinase. Future Oncol. 10, 957–967 (2014). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Ultimately, ARS-1620 was identified as the first KRAS(G12C) inhibitor suitable for in vivo studies and showed efficacy in KRAS(G12C) patient-derived xenograft models treated at 200 mg kg−1 once per day or twice per day87.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Covalent KRAS(G12C) inhibitors
What the sources say
- Not checked yetcites [87] Janes, M. R. et al. Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor. Cell 172, 578–589.e17 (2018). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Almost 50 years ago, this N-terminal amine was discovered to have a particularly low pKa of 6.9, indicating that it is primarily unprotonated under physiological conditions and, thus, more nucleophilic144.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Mutant-haemoglobin modulators
What the sources say
- Not checked yetcites [144] Garner, M. H., Bogardt, R. A. & Gurd, F. R. Determination of the pK values for the alpha-amino groups of human hemoglobin. J. Biol. Chem. 250, 4398–4404 (1975). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Many emerging covalent ligand screening platforms involve MS-based detection, enabled by covalent bond formation between the compound and protein.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Screening platforms
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“With a remarkable red blood cell to plasma ratio of ~150 that likely reduces off-target effects, voxelotor was approved by the FDA in 2019 with a recommended dose of 1.5 g daily, which is an unusually high dose for a covalent drug142,146.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Mutant-haemoglobin modulators
What the sources say
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Sickle cell anaemia is caused by a single mutation in the gene encoding the β-haemoglobin chain that induces polymerization of mutant haemoglobin (HbS) under hypoxic conditions142.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Mutant-haemoglobin modulators
What the sources say
- Not checked yetcites [142] Vichinsky, E. et al. A phase 3 randomized trial of voxelotor in sickle cell disease. N. Engl. J. Med. 381, 509–519 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Bortezomib (Takeda) was the first boron-containing drug to be approved by the FDA, and was approved for treatment of multiple myeloma in 2003 (ref.120).”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Covalent proteasome inhibitors
What the sources say
- Not checked yetcites [120] Bross, P. F. et al. Approval summary for bortezomib for injection in the treatment of multiple myeloma. Clin. Cancer Res. 10, 3954–3964 (2004). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“The resulting chloroacetamide sulfopin was shown to be selective for Pin1 in a covalent inhibitor target-site identification (CITe-Id) chemoproteomics experiment and was effective in regressing neuroblastoma growth in mice157.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Screening platforms
What the sources say
- Not checked yetcites [157] Dubiella, C. et al. Sulfopin is a covalent inhibitor of Pin1 that blocks Myc-driven tumors in vivo. Nat. Chem. Biol. 17, 954–963 (2021). source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Regardless, determination of kinact/Ki provides the most complete information to medicinal chemists about the binding affinity and kinetics of covalent target engagement.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Assaying for reactivity is a crucial step, particularly for key molecules and for compound series containing novel electrophiles.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Activity-based protein profiling (ABPP) approaches have transformed the characterization of electrophilic compounds, facilitating selectivity profiling and target identification experiments.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Based on earlier aldehydes, voxelotor was discovered through a structure-guided effort to discover compounds that increase the oxygen affinity of HbS, and was designed to bind the HbS tetramer in a 1:1 stoichiometry, unlike the 2:1 ratio of earlier compounds143,145.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Mutant-haemoglobin modulators
What the sources say
- Not checked yetcites [143] Metcalf, B. et al. Discovery of GBT440, an orally bioavailable r-state stabilizer of sickle cell hemoglobin. ACS Med. Chem. Lett. 8, 321–326 (2017). source
- Not checked yetcites [145] Oksenberg, D. et al. GBT 440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease. Br. J. Haematol. 175, 141–153 (2016). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This approach does not consider the reactivity of the electrophile, which can limit the ability to virtually study the differences in docking ligands with different electrophilic functional groups167.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Screening platforms
What the sources say
- Not checked yetcites [167] Scarpino, A., Ferenczy, G. G. & Keserű, G. M. Comparative evaluation of covalent docking tools. J. Chem. Inf. Model. 58, 1441–1458 (2018). This article compares the reproducibility of known binding data for covalent complexes across AutoDock4, CovDock, FITTED, GOLD, ICM-Pro and MOE docking programs. source
plainconditional- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Many covalent drug discovery programmes, including those for covalent EGFR and BTK inhibitors, have involved the addition of reactive functional groups to previously identified ligands.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The discovery of these covalent proteasome inhibitors illustrates the utility of boronic acid electrophiles for targeting protease active sites and demonstrates how a covalent drug discovery project can use an unoptimized electrophile as a starting point and subsequently introduce an alternative electrophile.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Covalent proteasome inhibitors
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Advances in chemoproteomics have facilitated the discovery of covalent ligands against undruggable disease targets and enabled the selectivity profiling of covalent ligands across the proteome to identify targets and off-targets of these ligands.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“These aldehydes bind in a reversible covalent manner, forming a Schiff base with the N-terminal valine of the α-haemoglobin chain143.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Mutant-haemoglobin modulators
What the sources say
- Not checked yetcites [143] Metcalf, B. et al. Discovery of GBT440, an orally bioavailable r-state stabilizer of sickle cell hemoglobin. ACS Med. Chem. Lett. 8, 321–326 (2017). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Voxelotor (Global Blood Therapeutics) is a lysine-targeting covalent drug used to treat sickle cell anaemia, and the discovery of voxelotor (Table 1) was dependent on knowledge of heightened lysine side chain reactivity.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Mutant-haemoglobin modulators
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The development of bortezomib validated the proteasome as a cancer target, encouraging the discovery of other proteasome inhibitors.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Covalent proteasome inhibitors
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“These boron-based drugs target serine hydrolases, and the weak boron–sulfur bond potentially provides selectivity for serine over cysteine hydrolases121.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Other boron-containing drugs
What the sources say
- Not checked yetcites [121] Adams, J. et al. Potent and selective inhibitors of the proteasome: dipeptidyl boronic acids. Bioorg. Med. Chem. Lett. 8, 333–338 (1998). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although targeting especially nucleophilic protease active sites might provide greater flexibility in terms of electrophile choice, using highly reactive electrophiles to gain an initial foothold can be beneficial.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Covalent proteasome inhibitors
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The growth of commercial libraries of electrophilic fragment-like compounds is a key factor contributing to the rise of these electrophile-first discovery strategies.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Screening platforms
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“For example, this type of approach proved successful in drugging KRAS(G12C) and has facilitated the rapid discovery of E3 ligase ligands for targeted protein degradation applications.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“this mechanism has been proposed to confer selectivity because most proteases do not have nucleophilic side chains at their N terminus127.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Covalent proteasome inhibitors
What the sources say
- Not checked yetcites [127] Groll, M., Kim, K. B., Kairies, N., Huber, R. & Crews, C. M. Crystal structure of epoxomicin:20S proteasome reveals a molecular basis for selectivity of α‘,β‘-epoxyketone proteasome inhibitors. J. Am. Chem. Soc. 122, 1237–1238 (2000). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“DNA-encoded libraries (DELs) present an alternative approach that enables the screening of massive libraries of small molecules. Unlike MS or ABPP approaches, there is no specialized advantage of covalency in enabling DEL screening”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Screening platforms
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“CovDock uses traditional non-covalent docking approaches to dock a ligand to a protein target, and then models the covalent bond attachment and refines the complex166.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Screening platforms
What the sources say
- Not checked yetcites [166] Sotriffer, C. Docking of covalent ligands: challenges and approaches. Mol. Inf. 37, 1800062 (2018). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Scientists working on a covalent JAK3 inhibitor programme at Pfizer, however, suggested that fixed-time-point IC50 values can serve as a valuable surrogate for kinact/Ki (ref. 218).”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox
What the sources say
- Not checked yetcites [218] Thorarensen, A. et al. The advantages of describing covalent inhibitor in vitro potencies by IC50 at a fixed time point. IC50 determination of covalent inhibitors provides meaningful data to medicinal chemistry for SAR optimization. Bioorg. Med. Chem. 29, 115865 (2021). source
hedgedcorrelational- Asserted: fails — The authors may not put it forward as true.
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Probably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Boceprevir and telaprevir were effective in treating HCV and were approved by the FDA in 2011 after successful trials115,116.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > HCV NS3/4a protease inhibitors
What the sources say
- Not checked yetcites [115] Kwo, P. Y. et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet 376, 705–716 (2010). source
- Not checked yetcites [116] Sherman, K. E. et al. Response-guided telaprevir combination treatment for hepatitis C virus infection. N. Engl. J. Med. 365, 1014–1024 (2011). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In 2019, isoTOP-ABPP was used to identify RNF114 as the target of the enone-containing natural product nimbolide, which was used to make bifunctional degraders of bromodomain-containing protein 4 (BRD4) and BCR–ABL187.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [187] Spradlin, J. N. et al. Harnessing the anti-cancer natural product nimbolide for targeted protein degradation. Nat. Chem. Biol. 15, 747–755 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“ABPP probes contain a warhead that covalently reacts with nucleophilic amino acids (such as cysteine) and a reporter handle to monitor probe binding, such as a fluorophore, biotin or alkyne moiety for subsequent click chemistry-enabled applications173 (Fig. 5a).”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [173] Cravatt, B. F., Wright, A. T. & Kozarich, J. W. Activity-based protein profiling: from enzyme chemistry to proteomic chemistry. Annu. Rev. Biochem. 77, 383–414 (2008). This review highlights the tools involved in ABPP and explains their corresponding applications. source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“a tandem mass tag (TMT)-based streamlined cysteine activity-based protein profiling (SLC-ABPP) methodology was designed and used to profile an electrophilic fragment library at an impressive depth of more than 8,000 reactive cysteine sites with a total instrument time of 18 min per compound183.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [183] Kuljanin, M. et al. Reimagining high-throughput profiling of reactive cysteines for cell-based screening of large electrophile libraries. Nat. Biotechnol. 39, 630–641 (2021). source
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Overall, reactivity profiling generates large quantities of information across thousands of proteins, ultimately providing a relatively unbiased picture of nucleophilic (usually cysteine) amino acid reactivity.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Beyond identifying the lipase ABHD6 as crucial for metastatic fitness, this approach enabled screening in a biological context more relevant to the disease state through adaptation of covalent ligand screening to a multiplexed in vivo phenotypic assay.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [186] Grüner, B. M. et al. An in vivo multiplexed small-molecule screening platform. Nat. Methods 13, 883–889 (2016). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“EN4 targets Cys171, which is located within a predicted intrinsically disordered region of MYC, and showed selectivity on a proteome-wide scale in profiling of more than 1,500 cysteines using competitive isoTOP-ABPP.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [179] Boike, L. et al. Discovery of a functional covalent ligand targeting an intrinsically disordered cysteine within MYC. Cell Chem. Biol. 28, 4–13 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This information can be used to either select for appropriate protein targets in drug discovery programmes or to identify allosteric sites on proteins of interest that may have previously been considered un-ligandable or undruggable.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In this study, more than 700 ligandable cysteines were identified, and information was provided about the proteome-wide selectivity of each covalent fragment in the library.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [180] Backus, K. M. et al. Proteome-wide covalent ligand discovery in native biological systems. Nature 534, 570–574 (2016). This work demonstrates how chemoproteomics can be paired with covalent ligand screening to identify the protein targets of covalent ligands in complex biological samples. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“IsoTOP-ABPP experiments also enabled the identification of the lipase ABHD6 as the target of hit compounds from this screen, even though ABHD6 was not previously known to have a role in metastasis or cancer progression.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [186] Grüner, B. M. et al. An in vivo multiplexed small-molecule screening platform. Nat. Methods 13, 883–889 (2016). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Covalent ligands are not only useful as functional inhibitors, but also have important roles in emerging induced proximity modalities.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Cys171 was initially identified as a ligandable hotspot on MYC through analysis of compiled cysteine-reactive chemoproteomics data, and this information spurred the subsequent search for a selective covalent ligand against that cysteine.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [179] Boike, L. et al. Discovery of a functional covalent ligand targeting an intrinsically disordered cysteine within MYC. Cell Chem. Biol. 28, 4–13 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In a separate study, scout fragments were used to construct bifunctional FKBP12 and BRD4 degraders, and the authors identified DCAF16 as the target E3 ligase responsible for degradation190.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
What the sources say
- Not checked yetcites [190] Zhang, X., Crowley, V. M., Wucherpfennig, T. G., Dix, M. M. & Cravatt, B. F. Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16. Nat. Chem. Biol. 15, 737–746 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Most bifunctional degraders recruit CRBN or VHL, but there are more than 600 E3 ligases with varying substrate scopes.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In general, target identification experiments using chemoproteomic platforms are crucial in investigating the mechanism of action of electrophilic compounds discovered through phenotypic assays.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“ABPP can also be used to identify off-targets and generally assess the selectivity of covalent molecules.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Chemoproteomics-enabled discovery
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Such ligands include a kinetic transthyretin stabilizer204, an isoform-selective PI3Kδ inhibitor205 and inhibitors of cyclin-dependent kinase 2 (CDK2)206 and Hsp90 (ref.207).”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Lysine-directed covalent ligands
What the sources say
- Not checked yetcites [204] Grimster, N. P. et al. Aromatic sulfonyl fluorides covalently kinetically stabilize transthyretin to prevent amyloidogenesis while affording a fluorescent conjugate. J. Am. Chem. Soc. 135, 5656–5668 (2013). source
- Not checked yetcites [205] Dalton, S. E. et al. Selectively targeting the kinome-conserved lysine of PI3Kδ as a general approach to covalent kinase inhibition. J. Am. Chem. Soc. 140, 932–939 (2018). source
- Not checked yetcites [206] Anscombe, E. et al. Identification and characterization of an irreversible inhibitor of CDK2. Chem. Biol. 22, 1159–1164 (2015). source
- Not checked yetcites [207] Cuesta, A., Wan, X., Burlingame, A. L. & Taunton, J. Ligand conformational bias drives enantioselective modification of a surface-exposed lysine on Hsp90. J. Am. Chem. Soc. 142, 3392–3400 (2020). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Cysteine's low abundance provides selectivity but restricts opportunities to covalently target specific proteins.
- Rests on an assumption: The ε-amino group of lysine is not nucleophilic enough under physiological conditions, so efficient lysine-targeting covalent ligands require unusually reactive lysines.
In the paper
“However, sulfonyl fluoride-based probes are not completely selective for lysine and have also been used to target tyrosine residues209.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Lysine-directed covalent ligands
What the sources say
- Not checked yetcites [209] Hett, E. C. et al. Rational targeting of active-site tyrosine residues using sulfonyl fluoride probes. ACS Chem. Biol. 10, 1094–1098 (2015). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Cysteine's low abundance provides selectivity but restricts opportunities to covalently target specific proteins.
- Rests on an assumption: The ε-amino group of lysine is not nucleophilic enough under physiological conditions, so efficient lysine-targeting covalent ligands require unusually reactive lysines.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Over the past decade, advances in covalent drug discovery have led to successful drugs, including inhibitors of EGFR, BTK, KRAS(G12C) and SARS-CoV-2 Mpro.”
§ Advances in covalent drug discovery > Outlook
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“a library of approximately 180 electrophiles was assembled and isoTOP-ABPP experiments then performed to assess the selectivity of different chemotypes and identify lysines ligandable with small molecules202.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Lysine-directed covalent ligands
What the sources say
- Not checked yetcites [202] Abbasov, M. E. et al. A proteome-wide atlas of lysine-reactive chemistry. Nat. Chem. 13, 1081–1092 (2021). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Cysteine's low abundance provides selectivity but restricts opportunities to covalently target specific proteins.
- Rests on an assumption: The ε-amino group of lysine is not nucleophilic enough under physiological conditions, so efficient lysine-targeting covalent ligands require unusually reactive lysines.
None of the sources cited for this claim have been checked yet.
In the paper
“Through isoTOP-ABPP experiments, more than 9,000 ligandable lysines were identified and more elaborated pentafluorophenol-containing or N-hydroxysuccinimide-ester-containing compounds could selectively label specific proteins of interest200,201.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Lysine-directed covalent ligands
What the sources say
- Not checked yetcites [200] Hacker, S. M. et al. Global profiling of lysine reactivity and ligandability in the human proteome. Nat. Chem. 9, 1181–1190 (2017). source
- Not checked yetcites [201] Ward, C. C., Kleinman, J. I. & Nomura, D. K. NHS-esters as versatile reactivity-based probes for mapping proteome-wide ligandable hotspots. ACS Chem. Biol. 12, 1478–1483 (2017). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Cysteine's low abundance provides selectivity but restricts opportunities to covalently target specific proteins.
- Rests on an assumption: The ε-amino group of lysine is not nucleophilic enough under physiological conditions, so efficient lysine-targeting covalent ligands require unusually reactive lysines.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Adoption of electrophile-first discovery strategies represents a notable shift in the field.”
§ Advances in covalent drug discovery > Outlook
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“This study yielded more broadly reactive electrophiles, such as dicarboxaldehydes, that could be used for further lysine profiling experiments, but also identified less-reactive electrophiles, including N-acyl-N-alkyl sulfonamides, which had been previously used as tools for bioconjugation in cells202,203.”
§ Advances in covalent drug discovery > The covalent drug discovery toolbox > Lysine-directed covalent ligands
What the sources say
- Not checked yetcites [202] Abbasov, M. E. et al. A proteome-wide atlas of lysine-reactive chemistry. Nat. Chem. 13, 1081–1092 (2021). source
- Not checked yetcites [203] Tamura, T. et al. Rapid labelling and covalent inhibition of intracellular native proteins using ligand-directed N-acyl-N-alkyl sulfonamide. Nat. Commun. 9, 1870 (2018). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Cysteine's low abundance provides selectivity but restricts opportunities to covalently target specific proteins.
- Rests on an assumption: The ε-amino group of lysine is not nucleophilic enough under physiological conditions, so efficient lysine-targeting covalent ligands require unusually reactive lysines.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Covalent drug discovery overcomes obstacles in designing ligands against otherwise undruggable protein targets.”
§ Advances in covalent drug discovery > Outlook
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The approvals of these drugs represent milestones that showcase the evolution of covalent drug discovery from a serendipitous effort to a field with established roadmaps for success.”
§ Advances in covalent drug discovery > Outlook
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
Each covalent drug candidate must balance reactivity, potency, and selectivity.
“each compound must balance reactivity, potency and selectivity.”
The paper relies on this without support.
Cysteine's low abundance provides selectivity but restricts opportunities to covalently target specific proteins.
“The low abundance of cysteine enables selectivity but limits opportunities for covalently targeting specific proteins of interest.”
The paper relies on this without support.
The ε-amino group of lysine is not nucleophilic enough under physiological conditions, so efficient lysine-targeting covalent ligands require unusually reactive lysines.
“Owing to the low nucleophilicity of the ε-amino group of lysine under physiological conditions, the discovery of efficient lysine-targeting covalent ligands requires identification of unusually reactive lysines.”
The paper relies on this without support.
Most protein-reactive covalent drugs are electrophilic so that they can react with nucleophilic amino acids.
“Most protein-reactive covalent drugs tend to be electrophilic, to enable reactions with nucleophilic amino acids.”
The paper relies on this without support.
Nucleophilic drugs can react with electrophilic cofactors and post-translational modifications.
“By contrast, nucleophilic drugs can react with electrophilic cofactors and post-translational modifications.”
The paper relies on this without support.
Most bifunctional degraders recruit CRBN or VHL, but there are more than 600 E3 ligases with varying substrate scopes.
“Although most bifunctional degrader molecules (proteolysis-targeting chimeras (PROTACs)) recruit the E3 ligases cereblon (CRBN) or von Hippel–Lindau (VHL) protein to degrade target proteins, there are more than 600 E3 ligases with varying substrate scopes.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Similar to the first-generation EGFR TKI, afatinib forms hydrogen bonds to the main chain of Met793 in the hinge region and interacts with hydrophobic regions. The furanyl group is exposed to the solvent, and the 3-chloro-4-fluorophenyl group is located near the “gatekeeper” residue.50”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [50]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Mutant-haemoglobin modulators
“Voxelotor (Global Blood Therapeutics) is a lysine-targeting covalent drug used to treat sickle cell anaemia, and the discovery of voxelotor (Table 1) was dependent on knowledge of heightened lysine side chain reactivity.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Mutant-haemoglobin modulators
“These aldehydes bind in a reversible covalent manner, forming a Schiff base with the N-terminal valine of the α-haemoglobin chain143.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Other boron-containing drugs
“These boron-based drugs target serine hydrolases, and the weak boron–sulfur bond potentially provides selectivity for serine over cysteine hydrolases121.”
§ Advances in covalent drug discovery > Discoveries by electrophile-first approaches > Other boron-containing drugs
“Tavaborole covalently binds to the 2′ and 3′ hydroxy groups on the 3′ terminus of leucyl-tRNA, trapping the tRNA–tavaborole adduct in the editing site of leucyl-tRNA synthetase to block protein synthesis138.”
Citations
Cites
Lynch, T. J., Bell, D. W., Sordella, R., Gurubhagavatula, S., Okimoto, R. A., Brannigan, B. W., Harris, P. L., Haserlat, S. M., Supko, J. G., Haluska, F. G., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa040938 · Cited by 11,486
EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy
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K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions
Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A., & Shokat, K. M. (2013) · Nature · doi:10.1038/nature12796 · Cited by 2,557
Yu, H. A., Arcila, M. E., Rekhtman, N., Sima, C. S., Zakowski, M. F., Pao, W., Kris, M. G., Miller, V. A., Ladanyi, M., & Riely, G. J. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-2246 · Cited by 2,454
Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19
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The Clinical KRAS(G12C) Inhibitor AMG 510 Drives Anti-Tumour Immunity
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Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia
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Research works printed but not linked: 1
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Metadata
- Authors
- Boike, L., Henning, N. J., & Nomura, D. K.
- Affiliations
- Innovative Genomics Institute (US)
- Corresponding author
- Nomura, Daniel K.
- Venue
- Nature Reviews Drug Discovery
- Published
- 2022-08-25
- Volume
- 21
- Issue
- 12
- Pages
- 881-898
- ISSN
- 1474-1776 (ISSN-L)
- 1474-1784
- PMC
- PMC9403961
- OpenAlex
- W4293084539
- Semantic Scholar
- b94c42b5629eb6be15dea45d3c538519c52f5ee7
- Cited by
- 823
- References
- 223
- Citations by year
- 2026: 172 · 2025: 256 · 2024: 236 · 2023: 147 · 2022: 12
- FWCI
- 15.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Reviews Drug Discovery (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Science Foundation
- Mark Foundation For Cancer Research
- National Institutes of Health
- National Cancer Institute (F31CA268278, R01CA240981, R35CA263814)
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Keywords
- covalent drug discovery, covalent inhibitors, chemoproteomics, KRAS G12C inhibitors, EGFR inhibitors, BTK inhibitors, reactive functional groups, target identification, selectivity profiling
- MeSH terms
- Agammaglobulinaemia Tyrosine Kinase, SARS-CoV-2, COVID-19 Drug Treatment, Humans, Ligands, Structure-Activity Relationship, Proto-Oncogene Proteins p21(ras), Protein Kinase Inhibitors, Drug Discovery, ErbB Receptors
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