Drug discovery considerations in the development of covalent inhibitors

Abstract

In recent years, the number of drug candidates with a covalent mechanism of action progressing through clinical trials or being approved by the FDA has increased significantly. And as interest in covalent inhibitors has increased, the technical challenges for characterizing and optimizing these inhibitors have become evident. A number of new tools have been developed to aid this process, but these have not gained wide-spread use. This review will highlight a number of methods and tools useful for prosecuting covalent inhibitor drug discovery programs.

Keywords: Activity-based protein profiling (ABPP); Click chemistry; Covalent inhibitor; Mechanism-based inhibitor; Targeted covalent inhibitor (TCI); Warhead reactivity; k(inact)/K(i).