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 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.
Brown et al. (Tue,) studied this question.