Design, synthesis, and biological evaluation of novel potent dual Mer/c-Met inhibitors based on structural optimization

Mer and c-Met kinases are frequently co-overexpressed in diverse malignancies, where their concurrent inhibition offers potential for synergetic antitumor efficacy while mitigating toxicity risks associated with single-target therapy. Building upon our previously identified lead compound, we designed and synthesized novel derivatives targeting dual Mer/c-Met inhibition. Among these, compound 17j emerged as a potent dual inhibitor, demonstrating IC₅₀ values of 1.00 ± 0.14 nM (Mer) and 19.00 ± 3.23 nM (c-Met). This agent exhibited robust antiproliferative activity against HCT116, A2780, and PC-3 Cancer cell lines, coupled with favorable safety profiles including hERG liability. Notably, 17j displayed exceptional metabolic stability in human liver microsomes (t_1/2 = 72.6 min) over compound 17c. Mechanistic studies confirmed its dose-dependent cytotoxicity and significant suppression of HCT116 cell migration. Collectively, these findings position 17j as a promising therapeutic candidate for Mer/c-Met driven cancers.

Anti-cancer; Dual inhibitor; Mer kinase; Structural optimization; c-Met kinase.