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Cited by 3,395Protein Degradation and InhibitorsUbiquitin and proteasome pathwaysChemical Synthesis and Analysis

PROTAC targeted protein degraders: the past is prologue

Open access
Békés, Miklós, Langley, David R., Crews, Craig M.·2022·Nature Reviews Drug Discovery
DOI 10.1038/s41573-021-00371-6PMC PMC8765495
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Abstract

Targeted protein degradation (TPD) is an emerging therapeutic modality with the potential to tackle disease-causing proteins that have historically been highly challenging to target with conventional small molecules. In the 20 years since the concept of a proteolysis-targeting chimera (PROTAC) molecule harnessing the ubiquitin–proteasome system to degrade a target protein was reported, TPD has moved from academia to industry, where numerous companies have disclosed programmes in preclinical and early clinical development. With clinical proof-of-concept for PROTAC molecules against two well-established cancer targets provided in 2020, the field is poised to pursue targets that were previously considered ‘undruggable’. In this Review, we summarize the first two decades of PROTAC discovery and assess the current landscape, with a focus on industry activity. We then discuss key areas for the future of TPD, including establishing the target classes for which TPD is most suitable, expanding the use of ubiquitin ligases to enable precision medicine and extending the modality beyond oncology. Targeted protein degradation with proteolysis-targeting chimeras (PROTACs) has the potential to tackle disease-causing proteins that have historically been highly challenging to target with conventional small molecules. This article summarizes the first two decades of PROTAC discovery and discusses key areas for the future of this therapeutic modality, including establishing the target classes for which it is most suitable and extending its application beyond oncology.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes 20 years of PROTAC targeted protein degradation, from the first small-molecule PROTAC in 2001 to clinical proof-of-concept in 2020 and a growing industry pipeline. It argues that TPD is poised to expand beyond oncology, to new E3 ligases, and to previously undrugged targets.

Key findings

  • The first fully synthetic PROTAC, Protac-1, was reported in 2001 and targeted METAP2 via β-TRCP; the field then moved from peptide-based bioPROTACs to fully synthetic small molecules, with the first heterobifunctional degraders ARV-110 and ARV-471 entering phase I trials in 2019.
  • In 2020, ARV-110 (AR degrader) was well tolerated up to 420 mg, showed target degradation in tumours and early antitumour activity, and began phase II ARDENT in October 2020 at 420 mg; ARV-471 (ER degrader) showed a manageable tolerability profile and a 42% clinical benefit rate in a heavily pretreated population, with better ER degradation than fulvestrant and other clinical-stage SERDs at the same stage.
  • By the end of 2021, at least 15 targeted protein degraders had entered the clinic, including heterobifunctional PROTACs and molecular glues; most early clinical PROTACs recruit CRBN, with DT2216 as a notable VHL-recruiting exception.
  • The review identifies future inflection points: defining target classes best served by degradation over inhibition, expanding the E3 ligase landscape beyond CRBN/VHL (with more than 600 human E3 ligases), extending TPD beyond oncology, and validating modalities beyond IMiDs and PROTACs.

Methods

  • Narrative review, not a systematic review, synthesizing the first two decades of PROTAC/TPD discovery and the current clinical landscape with a focus on industry activity.
  • Data sources are published literature, clinical trial registries/company disclosures, and tables of clinical-stage heterobifunctional PROTACs and molecular glues (Tables 1 and 2).
  • Main analysis is qualitative synthesis of mechanism, target selection, E3 ligase biology, clinical proof-of-concept, and future directions; no meta-analysis or primary experimental data are reported.

Limitations

  • The paper does not state a formal limitations section. Evident from the text: it is a narrative review without a systematic search strategy or quantitative synthesis.
  • Clinical data cited are early/interim phase I/II results and rapidly evolving; several compounds in Table 1 have undisclosed E3 ligases or are only in IND-enabling studies, limiting conclusions about the full clinical landscape.
  • The future outlook is explicitly author-perspective (“in our opinion”), so forward-looking statements are not evidence-based predictions.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41573-021-00371-6

Cites

254 of 254 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 253 cited sources checked · 0 supported · 0 flagged

  • Premisenone given

    Clinical proof-of-concept for PROTAC molecules against two well-established cancer targets (the oestrogen receptor and the androgen receptor) was provided in 2020.

    “With clinical proof-of-concept for PROTAC molecules against two well-established cancer targets provided in 2020, the field is poised to pursue targets that were previously considered ‘undruggable’.”
    • Also stated in: § Introduction · plain
      “in 2020, these trials provided the first clinical proof-of-concept for the modality against two well-established cancer targets: the oestrogen receptor (ER) and the androgen receptor (AR).”
    Quote in the paperSubstantial claim
  • Premisecitation

    The discovery of a peptide from hypoxia-inducible factor 1 subunit-α (HIF1α) that bound the E3 ligase von Hippel-Lindau tumour suppressor (VHL) led to the design of cell-penetrating PROTACs that degraded a range of POIs.

    “The subsequent discovery of a peptide from hypoxia-inducible factor 1 subunit-α (HIF1α) that bound the E3 ligase von Hippel–Lindau tumour suppressor (VHL)18,19 led to the design of cell-penetrating PROTACs that degraded a range of POIs.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [18] Hon, W. C. et al. Structural basis for the recognition of hydroxyproline in HIF-1 alpha by pVHL. Nature 417, 975–978 (2002). source

      Not checked in the free run.

    • cites [19] Min, J. H. et al. Structure of an HIF-1alpha-pVHL complex: hydroxyproline recognition in signaling. Science 296, 1886–1889 (2002). source

      Not checked in the free run.

  • Premisenone given

    In 2019, the first PROTAC molecules entered clinical testing.

    “In 2019, the first PROTAC molecules entered clinical testing; in 2020, these trials provided the first clinical proof-of-concept for the modality against two well-established cancer targets: the oestrogen receptor (ER) and the androgen receptor (AR).”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Protac-1 acted as a tether between METAP2 and β-TRCP, enabling the ligase to ubiquitylate METAP2 in extracts from unfertilized Xenopus laevis eggs.

    “Protac-1 acted as a tether between METAP2 and β-TRCP, enabling the ligase to ubiquitylate METAP2 in extracts from unfertilized Xenopus laevis eggs.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Sakamoto, K. M. et al. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc. Natl Acad. Sci. USA 98, 8554–8559 (2001). source

      Not checked in the free run.

  • Premisecitation

    The E3 ligase cereblon (CRBN) was identified as the target of thalidomide and its analogues lenalidomide and pomalidomide, which are known as immunomodulatory imide drugs (IMiDs) in the context of cancer therapy.

    “In parallel with the development of these early PROTAC molecules, the E3 ligase cereblon (CRBN) was identified as the target of thalidomide and its analogues lenalidomide and pomalidomide6, which are known as immunomodulatory imide drugs (IMiDs) in the context of cancer therapy.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Ito, T. et al. Identification of a primary target of thalidomide teratogenicity. Science 327, 1345–1350 (2010). source

      Not checked in the free run.

  • May combine two claims. 58
  • Classified as probably not a substantial claim. 48
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingcitation

    This construct rapidly degraded PCNA and maintained low levels of PCNA for the 10 days of doxycycline dosing.

    “This construct rapidly degraded PCNA and maintained low levels of PCNA for the 10 days of doxycycline dosing.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [219] Lim, S. et al. Exquisitely specific anti-KRAS biodegraders inform on the cellular prevalence of nucleotide-loaded states. ACS Cent. Sci. 7, 274–291 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In mice bearing xenograft pancreatic tumours, orthotopic injection of the Vif-based degrader was more efficacious than intraperitoneal injection, highlighting the need for better delivery methods to advance bioPROTACs from laboratory tools to therapeutics.

    “However, in mice bearing xenograft pancreatic tumours, orthotopic injection of the Vif-based degrader was more efficacious than intraperitoneal injection, highlighting the need for better delivery methods to advance bioPROTACs from laboratory tools to therapeutics.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [212] Pan, T. et al. A recombinant chimeric protein specifically induces mutant KRAS degradation and potently inhibits pancreatic tumor growth. Oncotarget 7, 44299–44309 (2016). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisenone given

    PROTACs are heterobifunctional small molecules consisting of two ligands joined by a linker: one ligand recruits and binds a protein of interest (POI) while the other recruits and binds an E3 ubiquitin ligase.

    “These are heterobifunctional small molecules consisting of two ligands joined by a linker: one ligand recruits and binds a protein of interest (POI) while the other recruits and binds an E3 ubiquitin ligase.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Molecular glues constitute another important therapeutic class of targeted protein degraders.

    “Molecular glues, based on the serendipitous discovery that thalidomide and its analogues act as degrader molecules, constitute another important therapeutic class1–8.”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [1] Surka, C. et al. CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells. Blood 137, 661–677 (2021). source

      Not checked in the free run.

    • cites [2] Hansen, J. D. et al. Discovery of CRBN E3 ligase modulator CC-92480 for the treatment of relapsed and refractory multiple myeloma. J. Med. Chem. 63, 6648–6676 (2020). source

      Not checked in the free run.

    • cites [3] Lu, G. et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 343, 305–309 (2014). source

      Not checked in the free run.

    • cites [4] Kronke, J. et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 343, 301–305 (2014). source

      Not checked in the free run.

    • cites [5] Kronke, J. et al. Lenalidomide induces ubiquitination and degradation of CK1alpha in del(5q) MDS. Nature 523, 183–188 (2015). source

      Not checked in the free run.

    • cites [6] Ito, T. et al. Identification of a primary target of thalidomide teratogenicity. Science 327, 1345–1350 (2010). source

      Not checked in the free run.

    • cites [7] Fischer, E. S. et al. Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature 512, 49–53 (2014). source

      Not checked in the free run.

    • cites [8] Chamberlain, P. P. & Hamann, L. G. Development of targeted protein degradation therapeutics. Nat. Chem. Biol. 15, 937–944 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Simultaneous binding of the POI and ligase by the PROTAC induces ubiquitylation of the POI and its subsequent degradation by the ubiquitin-proteasome system (UPS), after which the PROTAC is recycled to target another copy of the POI.

    “Simultaneous binding of the POI and ligase by the PROTAC induces ubiquitylation of the POI and its subsequent degradation by the ubiquitin–proteasome system (UPS), after which the PROTAC is recycled to target another copy of the POI (Fig. 1).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given

    Targeted protein degradation (TPD) is an emerging therapeutic modality with the potential to tackle disease-causing proteins that have historically been highly challenging to target with conventional small molecules.

    “Targeted protein degradation (TPD) is an emerging therapeutic modality with the potential to tackle disease-causing proteins that have historically been highly challenging to target with conventional small molecules.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Many disease-causing proteins are difficult to target with conventional small molecules because their active sites are broad, shallow pockets or their surfaces are smooth with few binding sites.

  • May combine two claims.

    Interpretationreasoning

    The catalytic-type mechanism of action and event-driven pharmacology distinguishes PROTACs from classical inhibitors, which have a one-to-one relationship with the POI and whose pharmacology is driven by stoichiometry and, usually, by interactions with a catalytic site.

    “It is this catalytic-type mechanism of action (MoA) and event-driven pharmacology that distinguishes PROTACs from classical inhibitors, which have a one-to-one relationship with the POI and whose pharmacology is driven by stoichiometry and, usually, by interactions with a catalytic site.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    In the 20 years since the concept of a PROTAC harnessing the ubiquitin-proteasome system to degrade a target protein was reported, TPD has moved from academia to industry, where numerous companies have disclosed programmes in preclinical and early clinical development.

    “In the 20 years since the concept of a proteolysis-targeting chimera (PROTAC) molecule harnessing the ubiquitin–proteasome system to degrade a target protein was reported, TPD has moved from academia to industry, where numerous companies have disclosed programmes in preclinical and early clinical development.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    In the same time frame, TPD molecules have progressed from being based on peptides to fully synthetic, rationally designed small molecules.

    “In the same time frame, TPD molecules have progressed from being based on peptides to fully synthetic, rationally designed small molecules.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Over the past two decades, evidence for the broad therapeutic potential of PROTACs and other TPD molecules has moved from studies in cell lysates and cell culture to studies in animals and animal models of disease.

    “Over the past two decades, evidence for the broad therapeutic potential of PROTACs and other TPD molecules has moved from studies in cell lysates and cell culture to studies in animals and animal models of disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Thalidomide analogues co-opt CRBN to target IKAROS family zinc finger 1 (IKZF1) and IKZF3 for degradation, and are now considered as pioneering examples of molecular glues.

    “These drugs co-opt CRBN to target IKAROS family zinc finger 1 (IKZF1) and IKZF3 for degradation3,4,24, and are now considered as pioneering examples of molecular glues.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [3] Lu, G. et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 343, 305–309 (2014). source

      Not checked in the free run.

    • cites [4] Kronke, J. et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 343, 301–305 (2014). source

      Not checked in the free run.

    • cites [24] Gandhi, A. K. et al. Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN). Br. J. Haematol. 164, 811–821 (2014). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Human immunodeficiency virus 1 (HIV-1) deploys its viral proteins Vpr and Vpx, to recruit DDB1 and CUL4-associated factor 1 (DCAF1) to target several different human proteins, including DNA repair proteins, for ubiquitylation.

    “Human immunodeficiency virus 1 (HIV-1) deploys its viral proteins Vpr and Vpx, to recruit DDB1 and CUL4-associated factor 1 (DCAF1) to target several different human proteins, including DNA repair proteins, for ubiquitylation237,238.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [237] Planelles, V. & Barker, E. Roles of Vpr and Vpx in modulating the virus-host cell relationship. Mol. Asp. Med. 31, 398–406 (2010). source

      Not checked in the free run.

    • cites [238] Yan, J. et al. HIV-1 Vpr reprograms CLR4(DCAF1) E3 ubiquitin ligase to antagonize exonuclease 1-mediated restriction of HIV-1 infection. mBio 9, e01732-18 (2018).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The discovery of small-molecule mimetics of the HIF1α peptide opened the door to the rational design of PROTACs based wholly on small molecular structures - for example, the first PROTACs based on the bromodomain protein inhibitor JQ1 that recruited VHL to degrade bromodomain-containing protein 4 (BRD4).

    “The discovery of small-molecule mimetics of the HIF1α peptide20,21 opened the door to the rational design of PROTACs based wholly on small molecular structures — for example, the first PROTACs based on the bromodomain protein inhibitor JQ1 that recruited VHL to degrade bromodomain-containing protein 4 (BRD4)22,23.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [20] Buckley, D. L. et al. Small-molecule inhibitors of the interaction between the E3 ligase VHL and HIF1alpha. Angew. Chem. Int. Ed. Engl. 51, 11463–11467 (2012). source

      Not checked in the free run.

    • cites [21] Buckley, D. L. et al. Targeting the von Hippel-Lindau E3 ubiquitin ligase using small molecules to disrupt the VHL/HIF-1alpha interaction. J. Am. Chem. Soc. 134, 4465–4468 (2012). source

      Not checked in the free run.

    • cites [22] Bondeson, D. P. et al. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat. Chem. Biol. 11, 611–617 (2015). source

      Not checked in the free run.

    • cites [23] Zengerle, M., Chan, K. H. & Ciulli, A. Selective small molecule induced degradation of the BET bromodomain protein BRD4. ACS Chem. Biol. 10, 1770–1777 (2015). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    At least two dozen viruses are known to hijack the human ubiquitin-proteasome system (UPS) to promote their own survival and replication.

    “At least two dozen viruses are known to hijack the human ubiquitin–proteasome system (UPS) to promote their own survival and replication10.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Verma, R., Mohl, D. & Deshaies, R. J. Harnessing the power of proteolysis for targeted protein inactivation. Mol. Cell 77, 446–460 (2020). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Ubiquitin-dependent proteolysis is a major pathway that degrades intracellular proteins as part of normal cellular maintenance processes.

    “Ubiquitin-dependent proteolysis is a major pathway that degrades intracellular proteins as part of normal cellular maintenance processes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Ciechanover, A., Orian, A. & Schwartz, A. L. Ubiquitin-mediated proteolysis: biological regulation via destruction. Bioessays 22, 442–451 (2000). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The E6 protein of human papillomavirus type 16 (HPV-16) and type 18 (HPV-18) recruits the human E3 ligase, ubiquitin-protein ligase E3A (UBE3A; also known as E6AP) to ubiquitylate p53, resulting in its degradation.

    “For example, the E6 protein of human papillomavirus type 16 (HPV-16) and type 18 (HPV-18) recruits the human E3 ligase, ubiquitin–protein ligase E3A (UBE3A; also known as E6AP) to ubiquitylate p53, resulting in its degradation236.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [236] Lou, Z. & Wang, S. E3 ubiquitin ligases and human papillomavirus-induced carcinogenesis. J. Int. Med. Res. 42, 247–260 (2014). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The human genome is estimated to encode more than 600 E3 ligases, each with specificity for a different subset of proteins.

    “The human genome is estimated to encode more than 600 E3 ligases15, each with specificity for a different subset of proteins.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Burslem, G. M. & Crews, C. M. Proteolysis-targeting chimeras as therapeutics and tools for biological discovery. Cell 181, 102–114 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Molecular glues promote ubiquitylation of a POI by enhancing a protein-protein interaction (PPI) between a ligase and a potential substrate.

    “Although not heterobifunctional in the manner of PROTAC molecules, molecular glues promote ubiquitylation of a POI by enhancing a protein–protein interaction (PPI) between a ligase and a potential substrate (Fig. 2; Box 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    PROTACs expand accessible targets beyond those druggable by traditional stoichiometric inhibition and provide novel ways to achieve selectivity.

    “This expands the accessible targets well beyond those that are druggable by traditional stoichiometric inhibition and provides novel ways to achieve selectivity.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    Traditional small-molecule drug discovery research for intracellular targets has often focused on developing high-affinity inhibitors that target either the active site or an allosteric site on an enzyme to shut down the function of the POI (occupancy-driven pharmacology).

    “To date, traditional small-molecule drug discovery research for intracellular targets has often focused on developing high-affinity inhibitors that target either the active site or an allosteric site on an enzyme to shut down the function of the POI (occupancy-driven pharmacology).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Incorporating a ligand into a PROTAC allows the POI to be degraded without requiring a large excess of drug, resulting in more complete target blockade and a wider therapeutic window.

    “By incorporating the ligand into a PROTAC, which often acts in an iterative or ‘pseudo-catalytic’ fashion by binding and facilitating the interaction of its ligase and POI targets, the POI can be degraded without requiring a large excess of drug, thereby resulting in more complete target blockade and a wider therapeutic window22,48.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [22] Bondeson, D. P. et al. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat. Chem. Biol. 11, 611–617 (2015). source

      Not checked in the free run.

    • cites [48] Mares, A. et al. Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2. Commun. Biol. 3, 140 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Interim data for ARV-471 revealed robust signals of clinical efficacy, with a 42% clinical benefit rate in a heavily pretreated population.

    “The interim data for ARV-471 revealed a manageable tolerability profile with robust signals of clinical efficacy41, a 42% clinical benefit rate in a heavily pretreated population and evidence of better ER degradation than fulvestrant and other clinical-stage selective ER degraders (SERDs) when compared at the same stage of development.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Snyder, L. B. et al. The discovery of ARV-471, an orally bioavailable estrogen receptor degrading PROTAC for the treatment of patients with breast cancer. In Proc. 112th Annual Meeting of the American Association for Cancer Research 1116 (AACR, 2021). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    PROTACs bring the degradation function to the target (event-driven pharmacology), negating the need for an active site and redefining undruggable targets as simply undrugged.

    “PROTACs bring the degradation function to the target (event-driven pharmacology), negating the need for an active site and redefining undruggable targets as simply undrugged.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Many disease-causing proteins are difficult to target with conventional small molecules because their active sites are broad, shallow pockets or their surfaces are smooth with few binding sites.

  • May combine two claims.

    Interpretationnone given

    Proteins with resistance mutations to targeted therapies, scaffolding functions, or considered undruggable with other modalities can be highly suitable PROTAC targets.

    “Proteins that have evolved resistance mutations to targeted therapies, proteins with scaffolding functions and proteins that are considered ‘undruggable’ with other modalities can also be highly suitable PROTAC targets.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The linker can contribute to PROTAC solution conformation and degradation efficiency (DC50/Dmax), and influence E3 ligase-POI interactions and presentation of the POI within the zone of ubiquitylation.

    “The linker can contribute to the PROTAC solution conformation68 and degradation efficiency (DC50/Dmax)69, and influence the E3 ligase–POI interactions and presentation of the POI within the zone of ubiquitylation (Fig. 5).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [68] Atilaw, Y. et al. Solution conformations shed light on PROTAC cell permeability. ACS Med. Chem. Lett. 12, 107–114 (2021). source

      Not checked in the free run.

    • cites [69] Cyrus, K. et al. Impact of linker length on the activity of PROTACs. Mol. Biosyst. 7, 359–364 (2011). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Schneider et al. based their analysis on availability of a small-molecule binder, endogenous ubiquitylation status, and target protein half-life.

    “They based their analysis on several aspects of protein degradation mentioned here, such as availability of a small-molecule binder against the target, information on the endogenous ubiquitylation status of the target and target protein half-life.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [70] Schneider, M. et al. The PROTACtable genome. Nat. Rev. Drug Discov. 20, 789–797 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    PROTACs that covalently bind an E3 ligase would reduce three-body assembly kinetics into a two-body problem and enhance catalytic efficiency.

    “whereas PROTACs that covalently bind an E3 ligase would reduce the three-body assembly kinetics into a two-body problem and enhance the catalytic efficiency.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Bensimon et al. developed d9A-2, a pomalidomide-based PROTAC that degraded SLC9A1 and other SLC9 family members, leading to impaired pH homeostasis and cytotoxicity in multiple cancer cell lines via UPS-dependent TPD.

    “Furthermore, they developed d9A-2, a pomalidomide-based PROTAC that degraded SLC family 9 member A1 (SLC9A1) — and, to a lesser extent, other SLC9 family members — leading to impaired pH homeostasis and cytotoxicity in multiple cancer cell lines, via a mechanism consistent with UPS-dependent TPD52.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Bensimon, A. et al. Targeted degradation of SLC transporters reveals amenability of multi-pass transmembrane proteins to ligand-induced proteolysis. Cell Chem. Biol. 27, 728–739 e729 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DT2216 uses VHL as the recruiting ligase and is in phase I trials.

    “A notable exception is a BCL-xL degrader known as DT2216 developed by Dialectic Therapeutics that uses VHL as the recruiting ligase77,78, which is in phase I trials (Table 1).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [77] He, Y. et al. DT2216-a Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas. J. Hematol. Oncol. 13, 95 (2020). source

      Not checked in the free run.

    • cites [78] Zhang, X. et al. Utilizing PROTAC technology to address the on-target platelet toxicity associated with inhibition of BCL-XL. Chem. Commun. 55, 14765–14768 (2019). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    To take full advantage of favourable PROTAC-induced E3-POI interactions, a wider set of PROTACable E3 ligases will be needed.

    “To take full advantage of favourable PROTAC-induced E3–POI interactions a wider set of PROTACable E3 ligases will be needed, as discussed in the next section.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Interpretationreasoning

    Degrader discovery has converged upon two main paths: an opportunistic approach and a rationally driven approach.

    “As noted earlier, degrader discovery has converged upon two main paths for discovering molecules that result in specific target degradation (Fig. 2; Box 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Nabet et al. developed a heterologous tagging platform, dTAG, that allows validation of unliganded or yet-to-be-liganded proteins as degradation targets and is enabled for both VHL and CRBN.

    “Nabet et al.53,95 have developed a heterologous tagging platform, dTAG, that allows validation of unliganded or yet-to-be-liganded proteins as degradation targets and is enabled for both VHL and CRBN.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [53] Nabet, B. et al. The dTAG system for immediate and target-specific protein degradation. Nat. Chem. Biol. 14, 431–441 (2018). source

      Not checked in the free run.

    • cites [95] Nabet, B. et al. Rapid and direct control of target protein levels with VHL-recruiting dTAG molecules. Nat. Commun. 11, 4687 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The modular nature of PROTACs and their ability to achieve near-immediate degradation of a wide range of target proteins allows rapid evaluation of basic degraders and characterization of their functions in cells through acute protein loss.

    “The modular nature of the modality and its ability to achieve near-immediate degradation of a wide range of target proteins allows rapid evaluation of such basic degraders and characterization of their functions in cells through acute protein loss.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The opportunity is ripe to tap into unexplored E3 ligases for protein degradation.

    “We would argue that the opportunity is ripe to tap into unexplored E3 ligases for protein degradation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    These challenges leave the door open to opportunities for identifying and developing alternative E3 ligases.

    “These and other challenges leave the door open to opportunities for identifying and developing alternative E3 ligases.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Ubiquitin E3 ligases serve as scaffolds between a target protein and an activated E2-Ub, binding both and catalysing transfer of ubiquitin from the E2 active site cysteine to a lysine on the target.

    “ubiquitin E3 ligases serve as scaffolds between a target protein and an activated ubiquitin E2 conjugating enzyme charged with a ubiquitin molecule (E2–Ub), by binding both molecules, then catalysing the transfer of ubiquitin from the active site cysteine of the E2 onto a lysine side chain of a target protein104–107.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [104] Zimmerman, E. S., Schulman, B. A. & Zheng, N. Structural assembly of cullin-RING ubiquitin ligase complexes. Curr. Opin. Struct. Biol. 20, 714–721 (2010). source

      Not checked in the free run.

    • cites [105] Duda, D. M. et al. Structural regulation of cullin-RING ubiquitin ligase complexes. Curr. Opin. Struct. Biol. 21, 257–264 (2011). source

      Not checked in the free run.

    • cites [106] Baek, K. et al. NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly. Nature 578, 461–466 (2020). source

      Not checked in the free run.

    • cites [107] Baek, K., Scott, D. C. & Schulman, B. A. NEDD8 and ubiquitin ligation by cullin-RING E3 ligases. Curr. Opin. Struct. Biol. 67, 101–109 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The proximity of KRAS to the membrane and the large size of the CUL4A-DDB1-CRBN-E2-Ub complex relative to the smaller CUL2-ELOB-ELOC-VHL-E2-Ub complex could be a contributing factor to the different outcomes.

    “Its proximity to the membrane and the large size of the Cullin 4A (CUL4A)–DDB1–CRBN–E2–Ub complex relative to the smaller CUL2–elongin B (ELOB)–ELOC–VHL–E2–Ub complex (Fig. 5) could be a contributing factor.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    CRBN and VHL are substrate receptor proteins that pair with CRL4 and CRL2, respectively.

    “CRBN and VHL, for example, are substrate receptor proteins that pair with CRL4 and CRL2, respectively.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    RBR ligases use a hybrid between the RING and HECT ligation strategies.

    “RBR ligases use a hybrid between the RING and HECT ligation strategies114,115.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [114] Yuan, L., Lv, Z., Atkison, J. H. & Olsen, S. K. Structural insights into the mechanism and E2 specificity of the RBR E3 ubiquitin ligase HHARI. Nat. Commun. 8, 211 (2017).

      Not checked in the free run.

    • cites [115] Dove, K. K. et al. Structural studies of HHARI/UbcH7~Ub reveal unique E2~Ub conformational restriction by RBR RING1. Structure 25, 890–900 e895 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cooperativity of the ternary complex may be positive or negative and has been shown to lead to degradation in both cases.

    “Cooperativity of the ternary complex, which is a measure of ternary complex formation in a heterobifunctional system, may be positive or negative between a ligase and a target enabled by a PROTAC molecule128 and has been shown to lead to degradation in both cases.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [128] Hughes, S. J. & Ciulli, A. Molecular recognition of ternary complexes: a new dimension in the structure-guided design of chemical degraders. Essays Biochem. 61, 505–516 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    KRAS(G12C) is specifically targetable via the PROTAC mechanism, but targetability depends on the choice of E3 ligase.

    “Collectively, these findings demonstrate that KRAS(G12C) is specifically targetable via the PROTAC mechanism, but that targetability depends on the choice of E3 ligase”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    LC-2 engaged endogenous KRAS(G12C), induced its poly-ubiquitylation and degraded it via the 20S proteasome.

    “LC-2 was able to engage endogenous KRAS(G12C), induce its poly-ubiquitylation and degrade it via the 20S proteasome.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Bond, M. J., Chu, L., Nalawansha, D. A., Li, K. & Crews, C. M. Targeted degradation of oncogenic KRAS(G12C) by VHL-recruiting PROTACs. ACS Cent. Sci. 6, 1367–1375 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    More than 600 E3 ligases in the human genome fall into different classes depending on which ubiquitin ligation strategy they use.

    “the more than 600 E3 ligases in the human genome fall into different classes, depending on which ubiquitin ligation strategy they use (reviewed in refs80,108–110).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [80] Schapira, M., Calabrese, M. F., Bullock, A. N. & Crews, C. M. Targeted protein degradation: expanding the toolbox. Nat. Rev. Drug. Discov. 18, 949–963 (2019). source

      Not checked in the free run.

    • cites [108] Yau, R. & Rape, M. The increasing complexity of the ubiquitin code. Nat. Cell Biol. 18, 579–586 (2016). source

      Not checked in the free run.

    • cites [109] Komander, D. & Rape, M. The ubiquitin code. Annu. Rev. Biochem. 81, 203–229 (2012). source

      Not checked in the free run.

    • cites [110] Zheng, N. & Shabek, N. Ubiquitin ligases: structure, function, and regulation. Annu. Rev. Biochem. 86, 129–157 (2017). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    HECT ligases bind the target then transfer ubiquitin onto themselves before transferring ubiquitin to the target.

    “The second class, HECT ligases, bind the target then use an intermediate strategy of transferring ubiquitin onto themselves before transferring ubiquitin to the target112,113.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [112] Zhang, W. et al. System-wide modulation of HECT E3 ligases with selective ubiquitin variant probes. Mol. Cell 62, 121–136 (2016). source

      Not checked in the free run.

    • cites [113] Kamadurai, H. B. et al. Mechanism of ubiquitin ligation and lysine prioritization by a HECT E3. eLife 2, e00828 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cooperativity plays a role in the efficiency of the VHL-BRD4 degrader MZ1, but is dispensable for CRBN-BRD4 degraders.

    “Cooperativity plays a role in the efficiency of the VHL–BRD4 degrader MZ1 (ref.129), but is dispensable for CRBN–BRD4 degraders130.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [129] Gadd, M. S. et al. Structural basis of PROTAC cooperative recognition for selective protein degradation. Nat. Chem. Biol. 13, 514–521 (2017). source

      Not checked in the free run.

    • cites [130] Nowak, R. P. et al. Plasticity in binding confers selectivity in ligand-induced protein degradation. Nat. Chem. Biol. 14, 706–714 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The degree of ternary complex formation may differ from substrate to substrate; a ternary complex that forms too efficiently and remains tightly bound will not lead to efficient degradation.

    “the degree of ternary complex formation may differ from substrate to substrate127; that is, a ternary complex that forms too efficiently and remains tightly bound will not lead to efficient degradation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [127] Rodriguez-Rivera, F. P. & Levi, S. M. Unifying catalysis framework to dissect proteasomal degradation paradigms. ACS Cent. Sci. 7, 1117–1125 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    XY-4-88 degraded a GFP-KRAS(G12C) fusion protein in a non-catalytic manner but could not degrade untagged, endogenous KRAS(G12C).

    “Although XY-4-88 was able to degrade a GFP–KRAS(G12C) fusion protein, albeit in a non-catalytic manner because it covalently bound the target, it could not degrade untagged, endogenous KRAS(G12C).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [124] Zeng, M. et al. Exploring targeted degradation strategy for oncogenic KRAS(G12C). Cell Chem. Biol. 27, 19–31 e16 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    XY-4-88 induced the CRBN-KRAS(G12C) complex but not its poly-ubiquitylation.

    “Subsequent studies revealed that XY-4-88 induced the CRBN–KRAS(G12C) complex, but not its poly-ubiquitylation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    RING and RBR ligases have recently been shown to work in unison to mediate substrate ubiquitylation in a site-specific manner.

    “RING and RBR ligases have recently been shown to work in unison to mediate substrate ubiquitylation in a site-specific manner116,117.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [116] Scott, D. C. et al. Two distinct types of E3 ligases work in unison to regulate substrate ubiquitylation. Cell 166, 1198–1214 e1124 (2016). source

      Not checked in the free run.

    • cites [117] Horn-Ghetko, D. et al. Ubiquitin ligation to F-box protein targets by SCF-RBR E3-E3 super-assembly. Nature 590, 671–676 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A recent massive kinase degradation study revealed the degradable kinome and a diversity of kinase-degrading profiles among E3 ligases.

    “a recent massive kinase degradation study using various kinase inhibitors as warheads has revealed the ‘degradable kinome’ and a diversity of kinase-degrading profiles among E3 ligases”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [126] Donovan, K. A. et al. Mapping the degradable kinome provides a resource for expedited degrader development. Cell 183, 1714–1731 e1710 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    KRAS is a small protein (189 amino acids) and, when farnesylated, is localized to the plasma membrane.

    “KRAS is a small protein (189 amino acids) and, when farnesylated, it is localized to the plasma membrane.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    FBXO44 is enriched in some tissues but not specific to any.

    “F-box protein 44 (FBXO44)150 that is enriched in some tissues but not specific to any151.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [150] Kumanomidou, T. et al. The structural differences between a glycoprotein specific F-box protein Fbs1 and its homologous protein FBG3. PLoS ONE 10, e0140366 (2015). source

      Not checked in the free run.

    • cites [151] Glenn, K. A., Nelson, R. F., Wen, H. M., Mallinger, A. J. & Paulson, H. L. Diversity in tissue expression, substrate binding, and SCF complex formation for a lectin family of ubiquitin ligases. J. Biol. Chem. 283, 12717–12729 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Tumour enrichment of E3 ligases provides only a potential window of opportunity for PROTACs and may not translate to a greatly expanded therapeutic index for pleiotropically toxic inhibitors converted into tumour-specific PROTACs.

    “One caveat for this group of ligases is that tumour enrichment provides only a potential window of opportunity for PROTACs, which may not translate to a greatly expanded therapeutic index for pleiotropically toxic inhibitors that are converted into tumour-specific PROTACs.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The intersection between practical and aspirational attributes of niche ligases with respect to novel degrader development is often minimal at best, offering high risk/high reward scenarios.

    “The intersection between the practical and aspirational attributes of these niche ligases with respect to novel degrader development is often minimal at best, thus offering high risk/high reward scenarios for PROTAC discovery and development of degraders that recruit such specialized ligases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    AlphaFold from DeepMind has made available high-quality predicted models across the proteome and serves as a major stepping stone in potentially enabling computer-aided drug discovery for many hitherto unreachable targets and ligases.

    “Alphafold from DeepMind has made available all their high-quality predicted models across the proteome (https://alphafold.ebi.ac.uk/) and now serves as a major stepping stone in potentially enabling computer-aided drug discovery for many hitherto unreachable targets and ligases.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [141] Tunyasuvunakool, K. et al. Highly accurate protein structure prediction for the human proteome. Nature 596, 590–596 (2021). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    PROTACs based on cell-cycle-associated tumour-enriched E3 ligases might exhibit toxicities associated with classical chemotherapeutic agents, but this remains to be tested.

    “PROTACs based on these ligases might therefore exhibit toxicities associated with classical chemotherapeutic agents, but this remains to be tested.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    The TPD field has matured to the point that strides are being taken to realize specificity goals and enable precision TPD (pTPD).

    “The TPD field has now matured to the point that strides are being taken to realize such specificity goals and enable precision TPD (pTPD).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Degradation of BCL-xL by the VHL-recruiting PROTAC DT2216 was spared in platelets, resulting in reduced platelet-driven toxicity and an improved therapeutic index compared with a BCL-xL inhibitor.

    “degradation of BCL-xL by the VHL-recruiting PROTAC DT2216 (ref.152) was spared in platelets, thus resulting in reduced platelet-driven toxicity and an improved therapeutic index compared with a BCL-xL inhibitor78,153.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [152] Khan, S. et al. A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nat. Med. 25, 1938–1947 (2019). source

      Not checked in the free run.

    • cites [78] Zhang, X. et al. Utilizing PROTAC technology to address the on-target platelet toxicity associated with inhibition of BCL-XL. Chem. Commun. 55, 14765–14768 (2019). source

      Not checked in the free run.

    • cites [153] Zhang, X. et al. Discovery of PROTAC BCL-XL degraders as potent anticancer agents with low on-target platelet toxicity. Eur. J. Med. Chem. 192, 112186 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    As many E3 ligases are multisubunit complexes, analysing expression levels of a single subunit is only part of the whole picture.

    “However, as many E3 ligases are multisubunit complexes, analysing expression levels of a single subunit is only part of the whole picture.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Specific targeting of a PROTAC molecule by tumour cells over adjacent, non-cancerous tissue or uptake by a given type of tumour-initiating cell may be achieved by targeting tumour-specific or tumour-enriched E3 ligases.

    “Another new frontier to explore for pTPD is specific targeting of a PROTAC molecule by tumour cells over adjacent, non-cancerous tissue or uptake by a given type of tumour-initiating cell, which may be achieved by targeting tumour-specific or tumour-enriched E3 ligases.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The MAGE family of ubiquitin E3 ligases, often called MAGE-RING ligases (MRLs), comprise proteins that serve as substrate-recruitment modules for other RING E3 ligases, adding to and/or altering the substrate specificity of their co-E3 ligases.

    “An example of such a family of ligases are the MAGE (melanoma antigen genes) family of ubiquitin E3 ligases, often referred to as the MAGE-RING ligases (MRLs), which comprise proteins that serve as substrate-recruitment modules for other RING E3 ligases156,157, adding to and/or altering the substrate specificity of their co-E3 ligases (reviewed elsewhere155,158).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [156] Yang, S. W. et al. A cancer-specific ubiquitin ligase drives mRNA alternative polyadenylation by ubiquitinating the mRNA 3′ end processing complex. Mol. Cell 77, 1206–1221 e1207 (2020). source

      Not checked in the free run.

    • cites [157] Pineda, C. T. et al. Degradation of AMPK by a cancer-specific ubiquitin ligase. Cell 160, 715–728 (2015). source

      Not checked in the free run.

    • cites [155] Weon, J. L. & Potts, P. R. The MAGE protein family and cancer. Curr. Opin. Cell Biol. 37, 1–8 (2015). source

      Not checked in the free run.

    • cites [158] Lee, A. K. & Potts, P. R. A comprehensive guide to the MAGE family of ubiquitin ligases. J. Mol. Biol. 429, 1114–1142 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Highly tumour-enriched and tumour-dependent E3 ligases and ligase adaptors tend to be associated with the cell cycle and are likely to have similar profiles in tumours and rapidly dividing non-cancerous cells such as bone marrow.

    “A second caveat is that highly tumour-enriched and tumour-dependent E3 ligases and ligase adaptors tend to be associated with the cell cycle — for example, CDC20 or S-phase kinase-associated protein 2 (SKP2) and others — and are likely to have similar profiles in tumours and rapidly dividing non-cancerous cells in the human body, such as in the bone marrow.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    KLHL40 and KLHL41 have a documented role in the biology of nemaline myopathy.

    “which have a documented role in the biology of nemaline myopathy146,147.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [146] Gupta, V. A. et al. Identification of KLHL41 mutations implicates BTB-kelch-mediated ubiquitination as an alternate pathway to myofibrillar disruption in nemaline myopathy. Am. J. Hum. Genet. 93, 1108–1117 (2013). source

      Not checked in the free run.

    • cites [147] Garg, A. et al. KLHL40 deficiency destabilizes thin filament proteins and promotes nemaline myopathy. J. Clin. Invest. 124, 3529–3539 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    PROTAC degraders have the ability to degrade the target completely, instead of only inhibiting its enzymatic function, which would not affect any scaffolding role that a target may have.

    “Another advantage of PROTAC degraders is their ability to degrade the target completely, instead of only inhibiting its enzymatic function, which would not affect any scaffolding role that a target may have.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    BTK is a well-established target in inflammation, as well as in oncology, with approved drugs in the clinic.

    “BTK is a well-established target in inflammation, as well as in oncology, with approved drugs in the clinic164,165”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [164] Dobrovolsky, D. et al. Bruton tyrosine kinase degradation as a therapeutic strategy for cancer. Blood 133, 952–961 (2019). source

      Not checked in the free run.

    • cites [165] Zarrin, A. A., Bao, K., Lupardus, P. & Vucic, D. Kinase inhibition in autoimmunity and inflammation. Nat. Rev. Drug Discov. 20, 39–63 (2021). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Given its potential to degrade any target of choice, the reach of TPD is extending further than oncology.

    “However, given its potential to degrade any target of choice, the reach of TPD is extending further than oncology.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: TPD has the potential to degrade any target of choice.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A BTK PROTAC from Nurix Therapeutics that targets haematological malignancies (NX-2127) is currently in a phase I trial.

    “A BTK PROTAC from Nurix Therapeutics that targets haematological malignancies (NX-2127) is currently in a phase I trial (Table 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Table 1

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The role of IRAK4 in inflammatory conditions, as well as in B cell lymphomas, is well established, and several inhibitors are currently in clinical trials in autoimmune indications.

    “but the role of IRAK4 in inflammatory conditions, as well as in B cell lymphomas, is well established, and several inhibitors are currently in clinical trials in autoimmune indications165,171.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [165] Zarrin, A. A., Bao, K., Lupardus, P. & Vucic, D. Kinase inhibition in autoimmunity and inflammation. Nat. Rev. Drug Discov. 20, 39–63 (2021). source

      Not checked in the free run.

    • cites [171] Wiese, M. D., Manning-Bennett, A. T. & Abuhelwa, A. Y. Investigational IRAK-4 inhibitors for the treatment of rheumatoid arthritis. Expert Opin. Investig. Drugs 29, 475–482 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Small-molecule-mediated activation of the immune response against tumours is a rich area of drug development.

    “Following in the footsteps of immunotherapy, small-molecule-mediated activation of the immune response against tumours is a rich area of drug development176,177.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [176] van der Zanden, S. Y., Luimstra, J. J., Neefjes, J., Borst, J. & Ovaa, H. Opportunities for small molecules in cancer immunotherapy. Trends Immunol. 41, 493–511 (2020). source

      Not checked in the free run.

    • cites [177] Kerr, W. G. & Chisholm, J. D. The next generation of immunotherapy for cancer: small molecules could make big waves. J. Immunol. 202, 11–19 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Two small-molecule TPD strategies have been reported to lower mHTT levels: a small-molecule glue approach inducing proximity between mHTT and MAP1LC3α to target it to autophagy for degradation; and small-molecule PROTACs that recruit mHTT aggregates to E3 ligases from the IAP family, causing proteasomal degradation of the mutant protein.

    “In fact, two small-molecule TPD strategies have been reported to lower mHTT levels: a small-molecule glue approach inducing the proximity between mHTT and microtubule-associated protein 1 light chain 3α (MAP1LC3α; also known as LC3) to target it to the autophagy pathway for degradation196; and small-molecule PROTACs that recruit mHTT aggregates to E3 ligases from the IAP family, causing the protea”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [196] Li, Z. et al. Allele-selective lowering of mutant HTT protein by HTT-LC3 linker compounds. Nature 575, 203–209 (2019). source

      Not checked in the free run.

    • cites [197] Tomoshige, S., Nomura, S., Ohgane, K., Hashimoto, Y. & Ishikawa, M. Discovery of small molecules that induce the degradation of huntingtin. Angew. Chem. Int. Ed. Engl. 56, 11530–11533 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A large PPI study in SARS-CoV-2-infected cells revealed several potential druggable pathways and proteins that may be exploited by repurposing inhibitors and that could potentially be addressed by SARS-CoV-2-targeting PROTAC molecules.

    “A large PPI study in SARS-CoV-2-infected cells revealed several potential druggable pathways and proteins that may be exploited by repurposing inhibitors199, and that could potentially be addressed by SARS-CoV-2-targeting PROTAC molecules.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [199] Gordon, D. E. et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 583, 459–468 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    A PROTAC approach may result in a cleaner inhibitory phenotype and better tolerability as a therapeutic agent.

    “a PROTAC approach may result in a cleaner inhibitory phenotype and better tolerability as a therapeutic agent.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Small-molecule probes against tau oligomeric species, such as 18F-T807, have been developed and are currently in use as clinical tau PET tracers.

    “However, small-molecule probes against tau oligomeric species, such as 18F-T807, have been developed and are currently in use as clinical tau PET tracers190.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [190] Chien, D. T. et al. Early clinical PET imaging results with the novel PHF-tau radioligand [F-18]-T807. J. Alzheimers Dis. 34, 457–468 (2013). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    These antiviral inhibitors could provide starting points for the development of antiviral PROTACs that target SARS-CoV-2.

    “These antiviral inhibitors could provide starting points for the development of antiviral PROTACs that target SARS-CoV-2.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    These targets are still susceptible to degradation by alternative PROTAC approaches, including bioPROTACs and hybrid PROTACs.

    “Even so, these targets are still susceptible to degradation by alternative PROTAC approaches, including bioPROTACs and hybrid PROTACs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A peptide-based α-synuclein degrader has been reported and was shown to protect neurons from α-synuclein overexpression-induced toxicity.

    “A peptide-based α-synuclein degrader (see below) has been reported and was shown to protect neurons from α-synuclein overexpression-induced toxicity193.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [193] Qu, J. et al. Specific knockdown of alpha-synuclein by peptide-directed proteasome degradation rescued its associated neurotoxicity. Cell Chem. Biol. 27, 763 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pfizer initiated a phase I trial of its orally bioavailable SARS-CoV-2 Mpro inhibitor PF-07321332 in healthy individuals in February 2021, followed by a phase II/III study, in which the first patient was dosed in September 2021.

    “Importantly, Pfizer initiated a phase I trial of its orally bioavailable SARS-CoV-2 Mpro inhibitor, PF-07321332 (NCT04756531) in healthy individuals in February 2021, followed by a phase II/III study, in which the first patient was dosed in September 2021 (NCT04960202).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites NCT04756531

      Not checked in the free run.

    • cites NCT04960202

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Huntington disease, poly-glutamine-expanded mHTT aggregates and accumulates.

    “In Huntington disease, poly-glutamine-expanded mHTT aggregates and accumulates194”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [194] MacDonald, M. E. et al. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72, 971–983 (1993). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tauopathies include neurological disorders such as Alzheimer disease, frontotemporal dementia and progressive supranuclear palsy, in which pathology is heavily associated with toxic accumulation of aberrant tau species, leading tau to aggregate into paired helical filaments and ultimately into neurofibrillary tangles that result in neuronal cell death.

    “Tauopathies include neurological disorders, such as Alzheimer disease, frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP)182, in which pathology is heavily associated with toxic accumulation of aberrant tau species, leading tau to aggregate into paired helical filaments and ultimately into neurofibrillary tangles that result in neuronal cell death183.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [182] Wang, Y. & Mandelkow, E. Tau in physiology and pathology. Nat. Rev. Neurosci. 17, 5–21 (2016). source

      Not checked in the free run.

    • cites [183] Goedert, M. Tau protein and neurodegeneration. Semin. Cell Dev. Biol. 15, 45–49 (2004). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    With the recent discontinuation of the phase III trial of tominersen, an HTT-lowering ASO, the PROTAC modality could provide a useful alternative route to pursue mHTT.

    “With the recent discontinuation of the phase III trial of tominersen, an HTT-lowering ASO that it was hoped could become the first disease-modifying therapy for Huntington disease, the PROTAC modality could provide a useful alternative route to pursue this key target.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    α-Synuclein and tau are both intrinsically disordered proteins with distinct conformations that probably drive their respective pathologies and for which induced proteolytic degradation could be disease-modifying.

    “α-Synuclein and tau are both intrinsically disordered proteins with distinct conformations that probably drive their respective pathologies and for which induced proteolytic degradation could be disease-modifying184.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [184] Chang, C. W., Shao, E. & Mucke, L. Tau: enabler of diverse brain disorders and target of rapidly evolving therapeutic strategies. Science 371, eabb8255 (2021). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    A key PROTAC property is the ability to degrade proteins that are not classically targetable by small-molecule inhibitors because they lack active sites.

    “A key PROTAC property is the ability to degrade proteins that are not classically targetable by small-molecule inhibitors because they lack active sites.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    α-Synuclein is a protein that can accumulate in the neurons of patients with Parkinson disease.

    “Other targets in neurology where a PROTAC modality may offer clear advantages over current therapeutic agents include α-synuclein, a protein that can accumulate in the neurons of patients with Parkinson disease192.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [192] Kotzbauer, P. T., Trojanowsk, J. Q. & Lee, V. M. Lewy body pathology in Alzheimer’s disease. J. Mol. Neurosci. 17, 225–232 (2001). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Tau in its monomeric form is an intrinsically disordered protein without clearly defined small-molecule binding pockets, which has made development of small-molecule inhibitors challenging.

    “Tau in its monomeric form is an intrinsically disordered protein without clearly defined small-molecule binding pockets, which has made development of small-molecule inhibitors challenging.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    One strategy has utilized such PET tracers by turning them into tool PROTAC molecules that target tau by recruiting CRBN, and these were shown to cause degradation of tau species in cell-based models of tauopathy.

    “In fact, one strategy has utilized such PET tracers by turning them into tool PROTAC molecules that target tau by recruiting CRBN, and these were shown to cause degradation of tau species in cell-based models of tauopathy191.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [191] Silva, M. C. et al. Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models. eLife 8, e45457 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pfizer developed an Mpro inhibitor prodrug, PF-07304814, which is given intravenously and entered clinical trials in hospitalized patients with COVID-19 in 2020.

    “Pfizer has also developed an Mpro inhibitor prodrug, PF-07304814 (ref.203), which is given intravenously and which entered clinical trials in hospitalized patients with COVID-19 in 2020 (NCT04535167).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [203] Boras, B. et al. Discovery of a novel inhibitor of coronavirus 3CL protease as a clinical candidate for the potential treatment of COVID-19. bioRxiv https://doi.org/10.1101/2020.09.12.293498 (2020). source

      Not checked in the free run.

    • cites NCT04535167

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Induced turnover of tau by the UPS, and the degradability of tau species, has been demonstrated by a tau-KEAP1 chimeric peptide PROTAC molecule, as well as by a VHL-tau PROTAC.

    “Importantly, induced turnover of tau by the UPS, and the degradability of tau species, has been demonstrated by a tau–kelch-like ECH-associated protein 1 (KEAP1) chimeric peptide PROTAC molecule188, as well as by a VHL–tau PROTAC189.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [188] Lu, M. et al. Discovery of a Keap1-dependent peptide PROTAC to knockdown Tau by ubiquitination-proteasome degradation pathway. Eur. J. Med. Chem. 146, 251–259 (2018). source

      Not checked in the free run.

    • cites [189] Wang, W. et al. A novel small-molecule PROTAC selectively promotes tau clearance to improve cognitive functions in Alzheimer-like models. Theranostics 11, 5279–5295 (2021). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    In the near term, bioPROTACs will be used as tool molecules to drive small-molecule PROTAC drug development.

    “In the near term, bioPROTACs will be used as tool molecules to drive small-molecule PROTAC drug development.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    Continued advances in nanoparticle drug delivery methods and viral vector gene delivery systems will play a major part in bringing these novel modalities to patients.

    “Continued advances in nanoparticle drug delivery methods and viral vector gene delivery systems will play a major part in bringing these novel modalities to patients.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Other groups have reported fusion bioPROTACs that degraded HER2, MYC and KRAS and demonstrated therapeutically relevant effects in human cancer cell lines and mouse xenograft tumour models overexpressing these POIs.

    “Since then, other groups have reported fusion bioPROTACs that degraded the cancer targets human epidermal growth factor receptor 2 (HER2), MYC and KRAS and demonstrated therapeutically relevant effects in human cancer cell lines and mouse xenograft tumour models overexpressing these POIs16,17,211,212.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [16] Ma, Y. et al. Targeted degradation of KRAS by an engineered ubiquitin ligase suppresses pancreatic cancer cell growth in vitro and in vivo. Mol. Cancer Ther. 12, 286–294 (2013). source

      Not checked in the free run.

    • cites [17] Hatakeyama, S., Watanabe, M., Fujii, Y. & Nakayama, K. I. Targeted destruction of c-Myc by an engineered ubiquitin ligase suppresses cell transformation and tumor formation. Cancer Res. 65, 7874–7879 (2005). source

      Not checked in the free run.

    • cites [211] Li, X. et al. Degradation of HER2 by Cbl-based chimeric ubiquitin ligases. Cancer Res. 67, 8716–8724 (2007). source

      Not checked in the free run.

    • cites [212] Pan, T. et al. A recombinant chimeric protein specifically induces mutant KRAS degradation and potently inhibits pancreatic tumor growth. Oncotarget 7, 44299–44309 (2016). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationnone given

    Chimeric bioPROTACs can potentially be delivered as gene products and intracellular levels controlled by finely tuned promoters.

    “Chimeric bioPROTACs can potentially be delivered as gene products and intracellular levels controlled by finely tuned promoters.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Small-molecule PROTACs have the potential for oral delivery, and cellular levels can be controlled by dosing.

    “Small-molecule PROTACs have the potential for oral delivery, and cellular levels can be controlled by dosing.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Although bioPROTACs, O'PROTACs and TRAFTACs have the potential to become therapeutic agents, delivery and dosing are key hurdles to overcome.

    “Although bioPROTACs, O’PROTACs and TRAFTACs have the potential to become therapeutic agents, delivery and dosing are key hurdles to overcome.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationreasoning

    This modality has the potential to offer patients new treatment options across diverse indications.

    “and we believe this modality has the potential to offer patients new treatment options across diverse indications.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    For undrugged targets for which small-molecule ligands have not yet been discovered or productive small-molecule binding sites do not exist, bioPROTACs have an advantage: undrugged targets often form PPIs that are difficult to block with traditional drugs, but their protein-binding domains offer starting points for assembling bioPROTACs to initiate the drug discovery process.

    “For undrugged targets for which small-molecule ligands have not yet been discovered or productive small-molecule binding sites do not exist, bioPROTACs have an advantage: undrugged targets often form PPIs that are difficult to block with traditional drugs, but their protein-binding domains offer starting points for assembling bioPROTACs to initiate the drug discovery process.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Like small-molecule PROTACs, bioPROTACs can be rapidly assembled to identify potent degraders if the warheads are known.

    “Like small-molecule PROTACs, bioPROTACs can be rapidly assembled to identify potent degraders if the warheads are known.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    bioPROTACs can be used to determine the biological benefit of complete inhibition of a protein via degradation versus partial inhibition with a small molecule; to compare the biological effect of post-expression degradation versus silencing expression with RNA interference; and to determine which face of the target protein is approachable by the E3 ligase and leads to productive lysine placement.

    “Therefore, bioPROTACs can be used for the following: to determine the biological benefit of complete inhibition of a protein via degradation versus partial inhibition with a small molecule; to compare the biological effect of post-expression degradation versus silencing expression with RNA interference; and to determine which face of the target protein is approachable by the E3 ligase and leads to”
    Quote in the paperSubstantial claim
97 of 97

  • The paper relies on this without support.

    Many disease-causing proteins are difficult to target with conventional small molecules because their active sites are broad, shallow pockets or their surfaces are smooth with few binding sites.

    “Some have been intractable because their active sites are broad, shallow pockets that are difficult to bridge with small molecules; others have ‘smooth’ surfaces that offer few sites for a small molecule to bind.”

  • The paper relies on this without support.

    For any new therapeutic modality, selecting well-known targets is important for establishing proof of concept because it introduces just one variable (the modality), not two.

    “For any new therapeutic modality, the selection of well-known targets is important for establishing proof of concept because it introduces just one variable (the modality), not two (the modality and a novel target) into the equation.”

  • The paper relies on this without support.

    Moderate affinity (≥1–500 nM) is typically needed for a ligand to be used in a PROTAC.

    “Using these sites does not require a high-affinity ligand if coupled to the right E3 ligand, but moderate affinity (≥1–500 nM) is typically needed”

  • The paper relies on this without support.

    Access to the POI surface near the binding site by a recruited E3 ligase is essential.

    “and access to the POI surface near the binding site by a recruited E3 ligase is essential.”

  • The paper relies on this without support.

    An ideal E3 ligase ligand would be a potent binder with a slow off-rate.

    “an ideal E3 ligase ligand would be a potent binder with a slow off-rate.”

  • The paper relies on this without support.

    Short linkers limit the number of ways the E3 ligase and POI come together and how the POI fits into the full E3–E2–ubiquitin complex.

    “However, short linkers limit the number of ways the E3 ligase and POI come together and, ultimately, how the POI fits into the full E3–E2–ubiquitin complex.”

  • The paper relies on this without support.

    Ternary complex formation is a necessary step in the action of a PROTAC molecule.

    “Ternary complex formation is a necessary step in the action of a PROTAC molecule”

  • The paper relies on this without support.

    Several ligases exist in an off state and are auto-inhibited in the absence of an activating post-translational modification or presence of a binding partner.

    “Several ligases exist in an ‘off’ state and are auto-inhibited in the absence of an activating post-translational modification or presence of a binding partner.”

  • The paper relies on this without support.

    TPD has the potential to degrade any target of choice.

    “given its potential to degrade any target of choice”

  • The paper relies on this without support.

    Some MAGE E3 ligases do not degrade their targets.

    “as some do not degrade their targets”

  • The paper relies on this without support.

    There are currently no approved IRAK4-targeting therapies.

    “By contrast, there are currently no approved IRAK4-targeting therapies”

  • The paper relies on this without support.

    HPK1 inhibitors are equally effective as HPK1-targeting PROTACs.

    “although HPK1 inhibitors were shown to be equally effective”

  • The paper relies on this without support.

    Transcription factors and RNA-binding proteins have largely remained undrugged because many lack ligand-binding sites.

    “Despite much effort, these POIs have largely remained undrugged as many of them lack ligand-binding sites.”
13 of 13

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?

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.

  • E6 is attributed to two different viruses

    Minor

    One passage identifies the p53-degrading E6 protein as belonging to human papillomavirus, while another attributes the E6 protein acting on p53 to hepatitis B virus.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Snyder, L. B. et al. Discovery of ARV-110, a first in class androgen receptor degrading PROTAC for the treatment of men with metastatic castration resistant prostate cancer. In Proc. 112th Annual Meeting of the American Association for Cancer Research 1115 (AACR, 2021).

Cited by

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Related

Authors
Békés, M., Langley, D. R., & Crews, C. M.
Affiliations
  • Arvinas (United States) (US)
  • Yale University (US)
Corresponding author
  • Békés, Miklós
  • Langley, David R.
  • Crews, Craig M.
ORCID
Venue
Nature Reviews Drug Discovery
Publisher
Springer Science and Business Media LLC
Published
2022-01-18
Volume
21
Issue
3
Pages
181-200
ISSN
  • 1474-1776 (ISSN-L)
  • 1474-1784
DOI
10.1038/s41573-021-00371-6
PMC
PMC8765495
OpenAlex
W4205379795
Semantic Scholar
4f8ace44d3e56b048f0dd996990cee73fed98aeb
Cited by
3,395
References
254
Citations by year
2026: 841 · 2025: 965 · 2024: 798 · 2023: 550 · 2022: 240 · 2014: 1
FWCI
67.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Reviews Drug Discovery (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Cancer Institute (R35CA197589)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
Keywords
PROTACs, targeted protein degradation, ubiquitin-proteasome system, ubiquitin ligase, undruggable targets, cancer therapeutics, precision medicine, drug discovery, pharmaceutical industry development
MeSH terms
Humans, Proteins, Proteasome Endopeptidase Complex, Proteolysis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

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