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

Wenjian Min; Yanyin Wang; Hongtao Shen; Mingming Zheng; Chen Tong; Hao Shen; Dawei Wang; Yasheng Zhu; Xiao Wang; Yibei Xiao; Xiao-Yu Zhang; Peng Yang

doi:10.1016/j.ejmech.2023.116025

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

Eur J Med Chem. 2024 Jan 15:264:116025. doi: 10.1016/j.ejmech.2023.116025. Epub 2023 Dec 5.

Authors

Wenjian Min¹, Yanyin Wang¹, Hongtao Shen², Mingming Zheng¹, Chen Tong², Hao Shen¹, Dawei Wang¹, Yasheng Zhu¹, Xiao Wang¹, Yibei Xiao³, Xiao-Yu Zhang⁴, Peng Yang⁵

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.

MeSH terms

Antineoplastic Agents* / chemistry
Carcinoma, Hepatocellular* / drug therapy
Carcinoma, Hepatocellular* / pathology
Carcinoma, Non-Small-Cell Lung*
Cell Line, Tumor
Cell Proliferation
Humans
Liver Neoplasms* / drug therapy
Liver Neoplasms* / pathology
Lung Neoplasms*
Protein Kinase Inhibitors / chemistry
Proto-Oncogene Proteins c-met

Substances

Proto-Oncogene Proteins c-met
Protein Kinase Inhibitors
Antineoplastic Agents