Covalent drug discovery: Progress against key targets, emerging strategies and lessons learnt

Abstract

Covalent drug discovery is currently experiencing a boom in industrial and academic interest. To date, at least 75 covalent drugs have received regulatory approval, 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 KRAS^G12C, EGFR^{L858R, T790M} and BTK, whilst molecules targeting KRAS^G12D, WRN helicase and p53^Y220C 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.

LINKED ARTICLES: This article is part of a themed issue Re-emergence of Covalent Modulation in Drug Discovery. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v183.22/issuetoc