Covalent chemical probes for protein kinases

Abstract

Small-molecule chemical probes are crucial tools to study the function of unexplored proteins in biological systems, thereby directly impacting preclinical target validation. Being one of the largest protein families in humans, protein kinases are currently among the most important and fruitful molecular targets in drug discovery. However, a significant fraction of the human “kinome” is still understudied and growing efforts in the scientific community aim at the development of specific chemical tool compounds for such “dark” kinases. Covalent targeting has proven to be a valid and rational strategy towards high-quality chemical probes enabling superior potencies, high selectivities and sustained target engagement. In the kinase field, the targeting of non-catalytic cysteine residues has been particularly fruitful and there is an increasing interest in addressing other residues, such as lysine or tyrosine. Herein, we discuss the properties and generation of covalent kinase inhibitors, with a special emphasis on electrophilic functional groups that can be used as “warheads”. Moreover, we highlight studies showcasing the development of covalent chemical probes targeting cysteine and lysine residues in an irreversible or reversible-covalent manner.