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

Han Yao; Yuanyuan Ren; Jun Yan; Jiadai Liu; Jinhui Hu; Ming Yan; Xingshu Li

doi:10.3390/molecules27175359

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

Molecules. 2022 Aug 23;27(17):5359. doi: 10.3390/molecules27175359.

Authors

Han Yao¹, Yuanyuan Ren¹, Jun Yan¹, Jiadai Liu¹, Jinhui Hu², Ming Yan¹, Xingshu Li¹

Affiliations

¹ School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
² School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China.

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.

Keywords: c-Met inhibitors; cancer; chiral compounds; kinase; tepotinib.

MeSH terms

Antineoplastic Agents* / pharmacology
Apoptosis*
Cell Cycle Checkpoints
Cell Proliferation
Drug Design
Drug Screening Assays, Antitumor
Molecular Structure
Protein Kinase Inhibitors / pharmacology
Structure-Activity Relationship

Substances

Antineoplastic Agents
Protein Kinase Inhibitors

Grants and funding

This work was financially supported by the Foundation of Guangdong Basic and Applied Basic Research (2019A1515110266), the Foundation for Young Talents (2019KQNCX159), and the Jiangmen Program for Young Talents (2019td04).