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

被引：2

作者：

Min, Wenjian ^{[1
,2
,3
]}

Yang, Huanaoyu ^{[1
,2
,3
]}

Wang, Dawei ^{[1
,2
,3
]}

Chen, Chunling ^{[1
,2
,3
]}

Wang, Yanyin ^{[1
,2
,3
]}

Hou, Yi ^{[1
,2
,3
]}

Zhu, Yasheng ^{[1
,2
,3
]}

Sun, Chengliang ^{[1
,2
,3
]}

Wang, Xiao ^{[1
,2
,3
]}

Yuan, Kai ^{[1
,2
,3
]}

Yang, Peng ^{[1
,2
,3
]}

机构：

[1] China Pharmaceut Univ, State Key Lab Nat Med, Jiangsu Key Lab Drug Design & Optimizat, Nanjing 210009, Peoples R China

[2] China Pharmaceut Univ, Sch Pharm, Dept Med Chem, Nanjing 211198, Peoples R China

[3] China Pharmaceut Univ, Inst Innovat Drug Discovery & Dev, Nanjing 211198, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2024年 / 67卷 / 14期

基金：

中国国家自然科学基金; 国家重点研发计划; 中国博士后科学基金;

关键词：

MEDIATED DEGRADATION; TARGET; CELL;

D O I：

10.1021/acs.jmedchem.4c01004

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：12314 / 12330

页数：17

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