Discovery of quinazoline-based dual RET/Aurora B inhibitors for non-small cell lung cancer.
TL;DR
The discovery of dual RET/AurB inhibitors with potent activity in NSCLC cells is reported, establishing a dual-targeted RET/AurB inhibition strategy that addresses complementary oncogenic vulnerabilities in NSCLC and provides a strong foundation for continued optimization and development.
Abstract
RET and Aurora B (AurB) kinases play critical roles in tumor growth and survival in non-small cell lung cancer (NSCLC), yet monotherapy approaches are frequently undermined by acquired resistance and tumor heterogeneity. Here, we report the discovery of dual RET/AurB inhibitors with potent activity in NSCLC cells. Structure-activity relationship (SAR) studies identified compound 47 as a lead candidate with nanomolar cellular potency. Compound 47 directly inhibits RET and Aurora B kinases in enzymatic assays and effectively suppresses their signaling in cells, as demonstrated by reduced phosphorylation levels. Mechanistic studies involving molecular modeling and kinetic analyses indicate that compound 47 functions as a type II RET inhibitor. In addition, compound 47 demonstrates favorable solubility at therapeutically relevant concentrations, which is further enhanced through salt formation. Collectively, these findings establish a dual-targeted RET/AurB inhibition strategy that addresses complementary oncogenic vulnerabilities in NSCLC and provides a strong foundation for continued optimization and development.