The structure based design of dual HDAC/BET inhibitors as novel epigenetic probes
The structure based design of dual HDAC/BET inhibitors as novel epigenetic probes
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DOI：
10.1039/c3md00285c
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发表时间：
2014-03-01
期刊：
影响因子：
--
通讯作者：
Prinjha, Rab K.
中科院分区：
文献类型：
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作者：
Atkinson, Stephen J.;Soden, Peter E.;Prinjha, Rab K.
在本论文中，我们设计并合成了一种具有双重活性的组蛋白脱乙酰酶(HDAC)/溴域和额外末端(BET)小分子toot抑制剂DUAL946(1)。利用我们广泛的表观遗传工具箱，我们实现了BET活性四氢喹啉(THQ)核心的功能化，带有异羟肟酸HDAC抑制剂(HDACi)基序。体外生化和生物物理实验以及细胞裂解物中的化学蛋白质组竞争实验证实了BET和HDAC蛋白的双重抑制作用。这种活性在免疫细胞和癌细胞中都转化为强大的细胞活性。
Herein we describe the design and synthesis of a dual active histone deacetylase (HDAC)/bromodomain and extra terminal (BET) small molecule toot inhibitor, DUAL946 (1). Exploiting our extensive epigenetic toolbox, we achieved the functionalisation of a BET active tetrahydroquinoline (THQ) core, with a hydroxamic acid HDAC inhibitor (HDACi) motif. Dual inhibition of BET and HDAC proteins was confirmed by in vitro biochemical and biophysical testing and through chemoproteomic competition experiments in cell lysates. This activity was translated into potent cellular activity in both immune and cancer cells.