Discovery of Potent and Selective c-Met Degraders for Hepatocellular Carcinoma Treatment,Journal of Medicinal Chemistry

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Discovery of Potent and Selective c-Met Degraders for Hepatocellular Carcinoma Treatment
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-07-04 , DOI: 10.1021/acs.jmedchem.4c01004
Wenjian Min _{1,

2,

3} , Huanaoyu Yang _{1,

2,

3} , Dawei Wang _{1,

2,

3} , Chunling Chen _{1,

2,

3} , Yanyin Wang _{1,

2,

3} , Yi Hou _{1,

2,

3} , Yasheng Zhu _{1,

2,

3} , Chengliang Sun _{1,

2,

3} , Xiao Wang _{1,

2,

3} , Kai Yuan _{1,

2,

3} , Peng Yang _{1,

2,

3}

Affiliation

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.

中文翻译：

发现用于肝细胞癌治疗的强效选择性 c-Met 降解剂

以c-Met为靶点是HCC精准治疗的临床趋势，但潜在的获得性耐药问题也不容忽视。靶向蛋白降解技术因其特殊的作用机制，在疾病治疗和克服耐药性方面展现出广阔的前景。在本研究中，我们设计并合成了两个系列的新型c-Met降解剂，并对最优化合物H11进行了系统的生物学评价。 H11表现出良好的c-Met降解活性和抗HCC活性。重要的是， H11还表现出比替泊替尼更有效的对 Ba/F3-TPR-MET-D1228N 和 Ba/F3-TPR-MET-Y1230H 细胞系的抑制活性。总之， H11作为降解剂表现出有效的抗 HCC 活性，并可能克服对 Ib 型抑制剂的耐药性，使其成为具有MET改变的 HCC 的新治疗策略。

更新日期：2024-07-04

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