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

ABSTRACT: 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 μM, compared to tepotinib (IC₅₀ = 0.013 μM). 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 G₁ phase in a dose-dependent fashion.

SUBMITTER: Yao H 

PROVIDER: S-EPMC9457593 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature