Covalent drug discovery: progress against key targets, emerging strategies and lessons learnt
Author(s)
Brown, Charlie
Armstrong, Alan
Mann, David
Type
Journal Article
Abstract
Covalent drug discovery is currently experiencing a boom in industrial and academic interest. To date, 75 covalent drugs have been approved by the FDA, targeting both
traditional target classes and more challenging proteins for which other approaches failed. In many cases, unique aspects of covalent targeting are essential for the
efficacy of the drug molecule. Famous successes include the discovery of therapies targeting KRASG12C, EGFRL858R, T790M and BTK; whilst molecules targeting KRASG12D, WRN helicase and p53Y220C have recently been disclosed and will represent significant
achievements if they receive regulatory approval. Increased interest in the field has catalysed innovation and advanced theoretical understanding of the distinct
considerations resulting from the covalent interaction. Here, we review progress against key covalent drug targets, emphasising notable molecules which exemplify the advantages of a covalent approach.
traditional target classes and more challenging proteins for which other approaches failed. In many cases, unique aspects of covalent targeting are essential for the
efficacy of the drug molecule. Famous successes include the discovery of therapies targeting KRASG12C, EGFRL858R, T790M and BTK; whilst molecules targeting KRASG12D, WRN helicase and p53Y220C have recently been disclosed and will represent significant
achievements if they receive regulatory approval. Increased interest in the field has catalysed innovation and advanced theoretical understanding of the distinct
considerations resulting from the covalent interaction. Here, we review progress against key covalent drug targets, emphasising notable molecules which exemplify the advantages of a covalent approach.
Date Issued
2026-02-24
Date Acceptance
2025-12-28
Citation
British Journal of Pharmacology, 2026
ISSN
0007-1188
Publisher
Wiley
Journal / Book Title
British Journal of Pharmacology
Copyright Statement
© 2026 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
License URL
Identifier
10.1111/bph.70344
Subjects
covalent drugs
drug discovery
irreverisble inhibition
small molecules
structure-based drug discovery
Publication Status
Published online
Date Publish Online
2026-02-24