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 in vitro. Furthermore, it exhibited favorable oral pharmacokinetic properties in mice, demonstrating superior in vivo efficacy compared to the multikinase inhibitor cabozantinib. In conclusion, compound 13 is a promising preclinical candidate.