Targeting the Protein Kinases Cysteinome

Apirat Chaikuad, Pierre Koch, Stefan Laufer, and Stefan Knapp

Angew. Chem. Int. Ed. 2017

doi: 10.1002/anie.201707875

Drugs that function by covalent bond formation represent a considerable fraction of our repository of effective medicines but safety concerns and the complexity of developing covalent inhibitors has rendered covalent targeting a less attractive strategy for rational drug design. The recent approval of four covalent kinase inhibitors and the development of highly potent covalent kinase probes with exceptional selectivity has raised significant interest in industry and academic research and validated the concept of covalent kinase targeting for clinical applications. The abundance of cysteines at diverse positions in and around the kinase active site suggests that a large fraction of kinases can be targeted by covalent inhibitors. Here we review recent developments of this rapidly growing area in kinase drug development and highlight the unique opportunities and challenges of this strategy.