Discovery of potent and selective c-Met inhibitors for MET-amplified hepatocellular carcinoma treatment

  • Eur J Med Chem. 2023 Dec 5:264:116025. doi: 10.1016/j.ejmech.2023.116025.
Wenjian Min  1 ,  Yanyin Wang  1 ,  Hongtao Shen  2 ,  Mingming Zheng  1 ,  Chen Tong  2 ,  Hao Shen  1 ,  Dawei Wang  1 ,  Yasheng Zhu  1 ,  Xiao Wang  1 ,  Yibei Xiao  3 ,  Xiao-Yu Zhang  4 ,  Peng Yang  5
Affiliations
  • 1. 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.
  • 2. State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
  • 3. State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing, 211198, China; Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: [email protected].
  • 4. 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. Electronic address: [email protected].
  • 5. 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. Electronic address: [email protected].
PMID: 38086189 DOI: 10.1016/j.ejmech.2023.116025
Abstract

Hepatocellular carcinoma (HCC) is a prevalent and lethal malignancy worldwide. The MET gene, which encodes receptor tyrosine kinase c-Met, is aberrantly activated in various solid tumors, including non-small cell lung Cancer and HCC. In this study, we identified a novel c-Met inhibitor 54 by virtual screening and structural optimization. Compound 54 showed potent c-Met inhibition with an IC50 value of 0.45 ± 0.06 nM. It also exhibited high selectivity among 370 kinases and potent anti-proliferative activity against MET-amplified HCC cells. Moreover, compound 54 displayed significant anti-tumor efficacy in vivo, making it a potential candidate for HCC treatment in future studies.

Keywords
Hepatocellular carcinoma; Selectivity; Structural optimization; c-Met inhibitor.
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