2. Academic Validation
  3. Discovery of potent and selective c-Met inhibitors for MET-amplified hepatocellular carcinoma treatment

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

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: yibei.xiao@cpu.edu.cn.
  • 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: xyzhang0918@163.com.
  • 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: pengyang@cpu.edu.cn.
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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