Reactivity-based chemical-genetic study of protein kinases.

The human protein kinase superfamily comprises over 500 members that operate in nearly every signal transduction pathway and regulate essential cellular processes. Deciphering the functional roles of protein kinases with small-molecule inhibitors is essential to enhance our understanding of cell signaling and to facilitate the development of new therapies. However, it is rather challenging to identify selective kinase inhibitors because of the conserved nature of the ATP binding site. A number of chemical-genetic approaches have been developed during the past two decades to enable selective chemical perturbation of the activity of individual kinases. Herein, we review the development and application of chemical-genetic strategies that feature the use of covalent inhibitors targeting cysteine residues to dissect the cellular functions of protein kinases. This journal is © The Royal Society of Chemistry.