Selective inhibition of BET bromodomains.
Selective inhibition of BET bromodomains.
复制标题
选择性抑制BET溴结构域。
作者：
表观遗传蛋白是配体发现的重要目标。迄今为止，成功的努力仅限于染色质修饰酶，或所谓的表观遗传“书写者”和“擦除者”。组蛋白结合模块的有效抑制剂尚未被描述。在这里，我们报告了一种细胞渗透性小分子（JQ1），它与乙酰赖氨酸识别基序或溴结构域竞争性结合。与BRD4的共晶结构解释了对人类溴结构域子集的高效和特异性，揭示了与乙酰赖氨酸结合腔的良好形状互补性。BRD4复发易位在一种基因定义的、无法治愈的人类鳞状癌亚型中被观察到。JQ1的竞争性结合取代了BRD4融合癌蛋白与染色质的结合，在BRD4依赖性细胞系和患者来源的异种移植模型中促进鳞状分化和特异性抗增殖作用。这些数据为靶向表观遗传“读者”的蛋白质-蛋白质相互作用的概念提供了证明，并为在整个溴域家族中更广泛地开发化学探针提供了一个通用的化学支架。
Epigenetic proteins are intently pursued targets in ligand discovery. To date, 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) which binds competitively to acetyl-lysine recognition motifs, or bromodomains. High potency and specificity toward a subset of human bromodomains is explained by co-crystal structures with 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 anti-proliferative 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.
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DOI：
10.1073/pnas.0708800104
发表时间：
2007-12-18
影响因子：
11.1
作者：
Fedorov, Oleg;Marsden, Brian;Knapp, Stefan
通讯作者：
Knapp, Stefan
影响因子：
5.6
作者：
Haack, Herbert;Johnson, Laura A.;French, Christopher A.
通讯作者：
French, Christopher A.
影响因子：
10.5
作者：
Peng, JM;Zhu, YR;Price, DH
通讯作者：
Price, DH
影响因子：
7.3
作者：
Bullock, AN;Debreczeni, JÉ;Knapp, S
通讯作者：
Knapp, S
影响因子：
3.3
作者：
Dey, Anup;Nishiyama, Akira;Ozato, Keiko
通讯作者：
Ozato, Keiko