Targeting epigenetic reader and eraser: Rational design, synthesis and in vitro evaluation of dimethylisoxazoles derivatives as BRD4/HDAC dual inhibitors
Targeting epigenetic reader and eraser: Rational design, synthesis and in vitro evaluation of dimethylisoxazoles derivatives as BRD4/HDAC dual inhibitors
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靶向表观遗传读取器和擦除器：二甲基异恶唑衍生物作为 BRD4/HDAC 双重抑制剂的合理设计、合成和体外评价
DOI：
10.1016/j.bmcl.2016.04.034
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发表时间：
2016
影响因子：
2.7
通讯作者：
Yadong Chen
中科院分区：
文献类型：
--
作者：
Zhimin Zhang;Shaohua Hou;Hongli Chen;Ting Ran;Fei Jiang;Yuanyuan Bian;Dewei Zhang;Yanle Zhi;Lu Wang;Li Zhang;Hongmei Li;Yanmin Zhang;Weifang Tang;Tao Lu;Yadong Chen
溴结构域蛋白模块和组蛋白脱乙酰酶（HDAC）分别识别和去除乙酰化赖氨酸，已经成为癌症治疗中重要的表观遗传治疗靶标。在本文中，我们提出了一种新的设计方法，用于癌症药物开发，通过在一个分子中组合溴结构域和HDAC抑制活性。合成了所设计的化合物，其显示出对溴结构域4和HDAC 1的抑制活性。代表性的双重布罗莫结构域/HDAC抑制剂化合物11和12在细胞测定中显示出对人白血病细胞系K562和MV 4 -11的有效抗增殖活性。本研究为开发具有潜在抗癌活性的溴结构域/HDAC双抑制剂奠定了基础。
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, compound11and12, 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.