Hinge binder modification into imidazopyridine for targeting actionable mutations of RET kinase

The RET proto-oncogene is a critical oncogenic driver in the development of several types of cancer. Despite the existence of clinically approved RET inhibitors, their limited response rates and emergence of resistance due to diverse actionable mutations underscore the need for novel therapeutics. Herein, we report substituted imidazo[1,2-<i>a</i>]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 cardiotoxicity was evaluated.