扰动染色质蛋白的小分子的发现，是当前生物医学研究中一个新兴的焦点。 在本期Nature上发表论文的两个小组以含“Bromodomain”的BET蛋白为研究目标，这些蛋白在基因激发过程中结合乙酰化的赖氨酸残迹，到达基于融合的“triazolo-diazepine”环的具有类似结构的、可透过细胞的小分子化合物上。James Bradner及其同事报告，他们研制出一种取名为JQ1的化合物。BET蛋白BRD4（带两个bromodomain）与人类鳞片状细胞癌有关。JQ1在小鼠模型中抑制依赖于BRD4的肿瘤的生长。Alexander Tarakhovsky及其同事发现，名为I-BET的抑制因子干涉BET家族某些成员与乙酰化组蛋白的结合。它抑制巨噬细胞中“促炎”基因的激发，在一个炎症小鼠模型中具有免疫调制活性。（生物谷Bioon.com）
生物谷推荐原文出处：
Nature doi:10.1038/nature09504
Selective inhibition of BET bromodomains
Panagis Filippakopoulos,Jun Qi,Sarah Picaud,Yao Shen,William B. Smith,Oleg Fedorov,Elizabeth M. Morse,Tracey Keates,Tyler T. Hickman,Ildiko Felletar,Martin Philpott,Shonagh Munro,Michael R. McKeown,Yuchuan Wang,Amanda L. Christie,Nathan West,Michael J. Cameron,Brian Schwartz,Tom D. Heightman,Nicholas La Thangue,Christopher A. French,Olaf Wiest,Andrew L. Kung,Stefan Knapp& James E. Bradner
Epigenetic proteins are intently pursued targets in ligand discovery. So far, successful efforts have been limited to chromatin modifying enzymes, or so-called epigenetic ‘writers’ and ‘erasers’. Potent inhibitors of histone binding modules have not yet been described. Here we report a cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains. High potency and specificity towards a subset of human bromodomains is explained by co-crystal structures with bromodomain and extra-terminal (BET) family member BRD4, revealing excellent shape complementarity with the acetyl-lysine binding cavity. Recurrent translocation of BRD4 is observed in a genetically-defined, incurable subtype of human squamous carcinoma. Competitive binding by JQ1 displaces the BRD4 fusion oncoprotein from chromatin, prompting squamous differentiation and specific antiproliferative effects in BRD4-dependent cell lines and patient-derived xenograft models. These data establish proof-of-concept for targeting protein–protein interactions of epigenetic ‘readers’, and provide a versatile chemical scaffold for the development of chemical probes more broadly throughout the bromodomain family.
