Hinge Binder Modification into Imidazopyridine for Targeting Actionable Mutations of RET Kinase

Abstract

The RET proto-oncogene plays a critical oncogenic driver in the development of several cancers. Despite the existence of clinically approved RET inhibitors, their limited response rates and the emergence of resistance due to diverse actionable mutations underscore the need for novel therapeutics. Herein, we report substituted imidazo[1,2-a]pyridine derivatives as new RET inhibitors exhibiting IC50 values as low as 11 nM against three distinct point mutations and three important RET fusions. The binding mode and measured potency were elucidated by induced-fit docking simulations and the safety for cardiotoxicity was further evaluated.