Discovery of Potent and Selective c-Met Degraders for Hepatocellular Carcinoma Treatment.

Autor: Min W; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China., Yang H; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China., Wang D; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China., Chen C; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China., Wang Y; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China., Hou Y; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China., Zhu Y; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China., Sun C; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China., Wang X; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China., Yuan K; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China., Yang P; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2024 Jul 25; Vol. 67 (14), pp. 12314-12330. Date of Electronic Publication: 2024 Jul 04.
DOI: 10.1021/acs.jmedchem.4c01004
Abstrakt: Targeting c-Met is a clinical trend for the precise treatment of HCC, but the potential issue of acquired drug resistance cannot be ignored. Targeted protein degradation technology has demonstrated promising prospects in disease treatment and overcoming drug resistance due to its special mechanism of action. In this study, we designed and synthesized two series of novel c-Met degraders and conducted a systematic biological evaluation of the optimal compound H11 . H11 exhibited good c-Met degradation activity and anti-HCC activity. Importantly, H11 also demonstrated more potent inhibitory activity against Ba/F3-TPR-MET-D1228N and Ba/F3-TPR-MET-Y1230H cell lines than did tepotinib. In summary, H11 displayed potent anti-HCC activity as a degrader and may overcome resistance to type Ib inhibitors, making it a new therapeutic strategy for HCC with MET alterations.
Databáze: MEDLINE
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