Structural Basis of Inhibitor Selectivity in the BRD7/9 Subfamily of Bromodomains.
Structural Basis of Inhibitor Selectivity in the BRD7/9 Subfamily of Bromodomains.
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DOI：
10.1021/acs.jmedchem.9b01980
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发表时间：
2020-03-26
影响因子：
7.3
通讯作者：
Schönbrunn E
中科院分区：
文献类型：
--
作者：
Karim RM;Chan A;Zhu JY;Schönbrunn E
通过小分子抑制含溴结构域蛋白9（BRD 9）是靶向癌症中突变的SWI/SNF染色质重塑复合物的有吸引力的策略。然而，报道的BRD 9抑制剂也抑制密切相关的含溴结构域蛋白7（BRD 7），其具有不同的生物学功能。由于缺乏BRD 7的结构信息，BRD 9抑制剂的不同效力和选择性的结构基础在很大程度上是未知的。在这里，我们在生物化学和结构上表征了不同的抑制剂，这些抑制剂对BRD 9的效力和选择性不同。与BRD 9和BRD 4一起确定了BRD 7与新的和先前报道的五种不同化学支架的抑制剂配体的新型共晶结构。我们还报告了在布罗莫结构域和末端外家族之外发现的第一个靶向BRD 7和BRD 9的双重布罗莫结构域激酶抑制剂。结合起来，这些数据为BRD 7/9抑制剂的开发提供了一个新的框架，具有更好的选择性或额外的多药理学特性。
Inhibition of the bromodomain containing protein 9 (BRD9) by small molecules is an attractive strategy to target mutated SWI/SNF chromatin-remodeling complexes in cancer. However, reported BRD9 inhibitors also inhibit the closely related bromodomain-containing protein 7 (BRD7), which has different biological functions. The structural basis for differential potency and selectivity of BRD9 inhibitors is largely unknown because of the lack of structural information on BRD7. Here, we biochemically and structurally characterized diverse inhibitors with varying degrees of potency and selectivity for BRD9 over BRD7. Novel cocrystal structures of BRD7 liganded with new and previously reported inhibitors of five different chemical scaffolds were determined alongside BRD9 and BRD4. We also report the discovery of first-in-class dual bromodomain—kinase inhibitors outside the bromodomain and extraterminal family targeting BRD7 and BRD9. Combined, the data provide a new framework for the development of BRD7/9 inhibitors with improved selectivity or additional polypharmacologic properties.
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