机构：[1]School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China[2]School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China[3]Department of Phase I Clinical Research Center, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, China广东省中医院[4]Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
Cellular mesenchymal-epithelial transition factor (c-Met), an oncogenic transmembrane receptor tyrosine kinase (RTK), plays an essential role in cell proliferation during embryo development and liver regeneration. Thioredoxin reductase (TrxR) is overexpressed and constitutively active in most tumors closely related to cancer recurrence. Multi-target-directed ligands (MTDLs) strategy provides a logical approach to drug combinations and would adequately address the pathological complexity of cancer. In this work, we designed and synthesized a series of selenium-containing tepotinib derivatives by means of selenium-based bioisosteric modifications and evaluated their antiproliferative activity. Most of these selenium-containing hybrids exhibited potent dual inhibitory activity toward c-Met and TrxR. Among them, compound 8b was the most active, with an IC50 value of 10 nM against MHCC97H cells. Studies on the mechanism of action revealed that compound 8b triggered cell cycle arrest at the G(1) phase and caused ROS accumulations by targeting TrxR, and these effects eventually led to cell apoptosis. These findings strongly suggest that compound 8b serves as a dual inhibitor of c-Met and TrxR, warranting further exploitation for cancer therapy.
基金：
Department of Education of Guangdong Province [2021ZDJS092]; Wuyi University; National College Students Innovation and Entrepreneurship Training Program [2021WGALH07]; Hong Kong & Macao Joint Research and Development Project; [S202111349099]
第一作者机构：[1]School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China
通讯作者：
推荐引用方式(GB/T 7714)：
Hu Jinhui,Chen Li,Lu Zhonghui,et al.Design, Synthesis and Antitumor Activity of Novel Selenium-Containing Tepotinib Derivatives as Dual Inhibitors of c-Met and TrxR[J].MOLECULES.2023,28(3):doi:10.3390/molecules28031304.
APA：
Hu, Jinhui,Chen, Li,Lu, Zhonghui,Yao, Han,Hu, Yunfei...&Chen, Wen-Hua.(2023).Design, Synthesis and Antitumor Activity of Novel Selenium-Containing Tepotinib Derivatives as Dual Inhibitors of c-Met and TrxR.MOLECULES,28,(3)
MLA：
Hu, Jinhui,et al."Design, Synthesis and Antitumor Activity of Novel Selenium-Containing Tepotinib Derivatives as Dual Inhibitors of c-Met and TrxR".MOLECULES 28..3(2023)
化学