Targeting epigenetic reader and eraser: Rational design, synthesis and in vitro evaluation of dimethylisoxazoles derivatives as BRD4/HDAC dual inhibitors

被引：54

作者：

Zhang, Zhimin ^{[1
]}

Hou, Shaohua ^{[1
]}

Chen, Hongli ^{[1
]}

Ran, Ting ^{[2
]}

Jiang, Fei ^{[1
]}

Bian, Yuanyuan ^{[1
]}

Zhang, Dewei ^{[1
]}

Zhi, Yanle ^{[1
]}

Wang, Lu ^{[1
]}

Zhang, Li ^{[1
]}

Li, Hongmei ^{[1
]}

Zhang, Yanmin ^{[2
]}

Tang, Weifang ^{[1
]}

Lu, Tao ^{[2
,3
]}

Chen, Yadong ^{[2
]}

机构：

[1] Sch Sci, Dept Organ Chem, 639 Longmian Ave, Nanjing 211198, Jiangsu, Peoples R China

[2] Sch Sci, Lab Mol Design & Drug Discovery, 639 Longmian Ave, Nanjing 211198, Jiangsu, Peoples R China

[3] China Pharmaceut Univ, State Key Lab Nat Med, 24 Tongjiaxiang, Nanjing 210009, Jiangsu, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2016年 / 26卷 / 12期

基金：

中国国家自然科学基金;

关键词：

Epigenetic; Protein-protein interactions; Bromodomain; HDAC; Antiproliferative activity; BROMODOMAIN; DISCOVERY;

D O I：

10.1016/j.bmcl.2016.04.034

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The bromodomain protein module and histone deacetylase ( HDAC), which recognize and remove acetylated lysine, respectively, have emerged as important epigenetic therapeutic targets in cancer treatments. Herein we presented a novel design approach for cancer drug development by combination of bromodomain and HDAC inhibitory activity in one molecule. The designed compounds were synthesized which showed inhibitory activity against bromodomain 4 and HDAC1. The representative dual bromodomain/HDAC inhibitors, compound 11 and 12, showed potent antiproliferative activities against human leukaemia cell line K562 and MV4-11 in cellular assays. This work may lay the foundation for developing dual bromodomain/HDAC inhibitors as potential anticancer therapeutics. (C) 2016 Elsevier Ltd. All rights reserved.

引用

页码：2931 / 2935

页数：5

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