Discovery of cysteine-targeting covalent histone methyltransferase inhibitors

Post-translational methylation of histone lysine or arginine residues by histone methyltransferases (HMTs) plays crucial roles in gene regulation and diverse physiological processes and is implicated in a plethora of human diseases, especially cancer. Therefore, histone methyltransferases have been increasingly recognized as potential therapeutic targets. Consequently, the discovery and development of histone methyltransferase inhibitors have been pursued with steadily increasing interest over the past decade. However, the disadvantages of limited clinical efficacy, moderate selectivity, and propensity for acquired resistance have hindered the development of HMTs inhibitors. Targeted covalent modification represents a proven strategy for kinase drug development and has gained increasing attention in HMTs drug discovery. In this review, we focus on the discovery, characterization, and biological applications of covalent inhibitors for HMTs with emphasis on advancements in the field. In addition, we identify the challenges and future directions in this fast-growing research area of drug discovery.