Discovery of Piperazine-Amide Derivatives as Highly Potent and Selective RET Inhibitors

Aberrant activation of the rearranged during transfection (RET) proto-oncogene is a key driver of various cancer types. Given the significant unmet clinical needs, the development of highly potent and selective RET inhibitors is urgent. Herein, we report a series of compounds featuring a novel piperazine-amide scaffold, designed and synthesized from BLU-667 via sequential bioisosteric replacement, linkage truncation, and subsequent structure-activity relationship (SAR) optimization. These efforts led to the identification of compound 13, which demonstrated exceptional inhibitory potency against wild-type RET kinase (IC₅₀ = 1.4 nM) and high selectivity (57-fold) over kinase insert domain receptor (KDR). Compound 13 also effectively suppressed the proliferation of cancer cell lines driven by activated RET mutations and gene fusions <i>in vitro</i>. Furthermore, it exhibited favorable oral pharmacokinetic properties in mice, demonstrating superior <i>in vivo</i> efficacy compared to the multikinase inhibitor cabozantinib. In conclusion, compound 13 is a promising preclinical candidate.