Discovery and Characterizatlion of Small Molecule Inhibitors of the BET Family Bromodomains
Discovery and Characterizatlion of Small Molecule Inhibitors of the BET Family Bromodomains
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DOI：
10.1021/jm200108t
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发表时间：
2011-06-09
影响因子：
7.3
通讯作者：
Nicodeme, Edwige
中科院分区：
文献类型：
--
作者：
Chung, Chun-wa;Coste, Herve;Nicodeme, Edwige
基因调控的表观遗传机制在正常发育和疾病过程中具有深远的作用。这一机制的一个组成部分是通过组蛋白尾部的赖氨酸乙酰化发生的，组蛋白尾部被溴域识别。虽然许多含有溴域的蛋白质的生物学和结构特征已经有了相当大的进步，但这个蛋白质家族的治疗可控性直到现在才变得清楚。本文描述了有效的(NM)小分子抑制剂的发现和分子特征，这些小分子抑制剂可以破坏BET家族溴结构域(Brd2、Brd3和Brd4)的功能。通过结合表型筛选、化学蛋白质组学和生物物理研究，我们发现溴结构域和乙酰化组蛋白之间的蛋白质相互作用可以被结合在乙酰化赖氨酸识别口袋上的选择性小分子拮抗。结合在Brd2和Brd4溴结构域中的化合物的X射线晶体结构解释了结合的分子相互作用，并解释了活性所需的精确定义的立体化学。
Epigenetic mechanisms of gene regulation have a profound role in normal development and disease processes. An integral part of this mechanism occurs through lysine acetylation of histone tails which are recognized by bromodomains. While the biological and structural characterization of many bromodomain containing proteins has advanced considerably, the therapeutic tractability of this protein family is only now becoming understood. This paper describes the discovery and molecular characterization of potent (nM) small molecule inhibitors that disrupt the function of the BET family of bromo domains (Brd2, Brd3, and Brd4). By using a combination of phenotypic screening, chemoproteomics, and biophysical studies, we have discovered that the protein protein interactions between bromodomains and acetylated histones can be antagonized by selective small molecules that bind at the acetylated lysine recognition pocket. X-ray crystal structures of compounds bound into bromodomains of Brd2 and Brd4 elucidate the molecular interactions of binding and explain the precisely defined stereochemistry required for activity.