Design, Synthesis, and Biological Evaluation of the First c-Met/HDAC Inhibitors Based on Pyridazinone Derivatives

被引：45

作者：

Lu, Dong ^{[1
,3
]}

Yan, Juan ^{[2
,3
]}

Wang, Lang ^{[1
]}

Liu, Hongchun ^{[2
]}

Zeng, Limin ^{[1
]}

Zhang, Minmin ^{[2
]}

Duan, Wenwen ^{[1
]}

Ji, Yinchun ^{[2
]}

Cao, Jingchen ^{[2
]}

Geng, Meiyu ^{[2
]}

Shen, Aijun ^{[2
]}

Hu, Youhong ^{[1
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, State Key Lab Drug Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China

[2] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China

[3] Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2017年 / 8卷 / 08期

基金：

中国国家自然科学基金;

关键词：

Dual c-Met/HDAC inhibitor; hybrid; designed multiple ligand (DML); HISTONE DEACETYLASE; HDAC; KINASE; PATHWAY; GROWTH;

D O I：

10.1021/acsmedchemlett.7b00172

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Simultaneous blockade of more than one pathway is considered to be a promising approach to overcome the low efficacy and acquired resistance of cancer therapies. Thus, a novel series of c-Met/HDAC bifunctional inhibitors was designed and synthesized by merging pharmacophores of c-Met and HDAC inhibitors. The most potent compound, 2m, inhibited c-Met kinase and HDAC1, with IC50 values of 0.71 and 38 nM, respectively, and showed efficient antiproliferative activities against both EBC-1 and HCT-116 cells with greater potency than the reference drug Chidamide. Western blot analysis revealed that compound 2m inhibited phosphorylation of c-Met and c-Met downstream signaling proteins and increased expression of Ac-H3 and p21 in EBC-1 cells in a dose-dependent manner. Our study presents novel compounds for the further exploration of dual c-Met/HDAC pathway inhibition achieved with a single molecule.

引用

页码：830 / 834

页数：5

共 31 条

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