Design, Synthesis, and Evaluation of New Mesenchymal-Epithelial Transition Factor (c-Met) Kinase Inhibitors with Dual Chiral Centers

A series of tepotinib derivatives with two chiral centers was designed, synthesized, and evaluated as anticancer agents. The optimal compound (R, S)-12a strongly exhibited antiproliferative activity against MHCC97H cell lines with an IC50 value of 0.002 mu M, compared to tepotinib (IC50 = 0.013 mu M). Mechanistic studies revealed that compound (R, S)-12a significantly inhibited c-Met activation, as well as the downstream AKT signaling pathway, and suppressed wound closure. Moreover, compound (R, S)-12a induced cellular apoptosis and cell cycle arrest at the G(1) phase in a dose-dependent fashion.

Automated summary

A series of tepotinib derivatives with two chiral centers were designed and synthesized as anticancer agents. Among them, the optimal compound (R, S)-12a exhibited strong antiproliferative activity against MHCC97H cell lines by inhibiting c-Met activation and the downstream AKT signaling pathway, suppressing wound closure, inducing cellular apoptosis, and arresting cell cycle at the G(1) phase in a dose-dependent fashion.