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

European journal of medicinal chemistry 2024 Jan 15

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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. Copyright © 2023 Elsevier Masson SAS. All rights reserved.

Citation

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. Discovery of potent and selective c-Met inhibitors for MET-amplified hepatocellular carcinoma treatment. European journal of medicinal chemistry. 2024 Jan 15;264:116025