Recent Advances in Selective and Irreversible Covalent Ligand Development and Validation
Open accessAbstract
Some of the most widely used drugs, such as aspirin and penicillin, are covalent drugs. Covalent binding can improve potency, selectivity, and duration of the effects, but the intrinsic reactivity represents a potential liability and may result in idiosyncratic toxicity. For decades, the cons were believed to outweigh the pros, and covalent targeting was deprioritized in drug discovery. Recently, several covalent inhibitors have been approved for cancer treatment, thus rebooting the field. In this review, we briefly reflect on the history of selective covalent targeting, and provide a comprehensive overview of emerging developments from a chemical biology stand-point. Our discussion will reflect on efforts to validate irreversible covalent ligands, expand the scope of targets, and discover new ligands and warheads. We conclude with a brief commentary of remaining limitations and emerging opportunities in selective covalent targeting.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
Covalent inhibitors bind to amino acid residues of target proteins through covalent bonds formed by mildly reactive functional groups to confer additional affinity compared to non-covalent inhibitors.
“Covalent inhibitors, also known as irreversible inhibitors, are a class of inhibitors that bind to amino acid residues of target proteins through covalent bonds formed by mildly reactive functional groups to confer additional affinity, compared to that of non-covalent inhibitors, which achieve binding and inhibition of target proteins through non-covalent interactions such as hydrogen bond and van”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [29]
Prolonged target engagement of covalent drugs can give distinct pharmacodynamic profiles and exceptional potency.
“The prolonged target engagement of covalent drugs can provide distinct pharmacodynamic profiles and exceptional potency6.”
From Advances in covalent drug discovery (2022) · cites this paper as [6]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 88 · Cited by 178
Research works printed but not linked: 1
- Ward CC, Kleinman JI, Brittain SM, Lee PS, Chung CYS, Kim K, Petri Y, Thomas JR, Tallarico JA, McKenna JM, Schirle M, Nomura DK, 2018 Covalent Ligand Screening Uncovers a RNF4 E3 Ligase Recruiter for Targeted Protein Degradation Applications. bioRxiv. 10.1101/439125 PMC7422721 31059647 · DOI
- Authors
- Zhang, T., Hatcher, J. M., Teng, M., Gray, N. S., & Kostic, M.
- Affiliations
- Harvard University (US)
- Corresponding author
- Gray, Nathanael S.
- Venue
- Cell Chemical Biology
- Publisher
- Elsevier BV
- Published
- 2019-11
- Volume
- 26
- Issue
- 11
- Pages
- 1486-1500
- ISSN
- 2451-9448 (ISSN-L)
- 2451-9456
- PMC
- PMC6886688
- OpenAlex
- W2980410567
- Cited by
- 178
- References
- 88
- Citations by year
- 2026: 21 · 2025: 21 · 2024: 27 · 2023: 25 · 2022: 37 · 2021: 25 · 2020: 21 · 2018: 1
- FWCI
- 1.59
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell chemical biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- covalent drug design, covalent inhibitors, warheads, chemical biology, drug selectivity, idiosyncratic toxicity, anticancer drug discovery
- MeSH terms
- Humans, Ligands, Lysine, Pyrimidines, Tyrosine, Cyclin-Dependent Kinases, Protein Kinase Inhibitors
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
