NMR Fragment Screening Hit Induces Plasticity of BRD7/9 Bromodomains
NMR Fragment Screening Hit Induces Plasticity of BRD7/9 Bromodomains
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DOI：
10.1002/cbic.201600184
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发表时间：
2016-08
期刊：
影响因子：
3.2
通讯作者：
Na Wang;Fudong Li;Hongyu Bao;Jie Li;Jihui Wu;K. Ruan
中科院分区：
文献类型：
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作者：
Na Wang;Fudong Li;Hongyu Bao;Jie Li;Jihui Wu;K. Ruan
与通过化学探针抑制溴结构域和额外末端（BET）结构域相关的复杂生物学已经引起越来越多的关注，并且需要鉴定非BET溴结构域（BD）抑制剂。最近发现了BRD 9 BD的几种有效抑制剂，具有抗癌和抗炎活性。然而，它的paradise，BRD 7 BD，仍然未开发。在这里，我们通过使用基于NMR片段的筛选鉴定了靶向BRD 7 BD的新化学型。BRD 7/9 BD在滴定命中化合物1时表现出类似的化学位移扰动模式。晶体结构显示，1以与丁酰赖氨酸类似的方式排斥BRD 9 BD的Y222基团，但不排斥乙酰赖氨酸和已知的抑制剂。与乙酰基赖氨酸、丁酰赖氨酸和巴豆酰赖氨酸相比，Hit 1诱导的BRD 9 BD残基F161重排较少。我们的研究为探索BRD 7/9 BD的功能提供了新一代丁酰赖氨酸模拟物的结构见解。
The complex biology associated with inhibition of bromodomain and extra‐terminal (BET) domains by chemical probes has attracted increasing attention, and there is a need to identify non‐BET bromodomain (BD) inhibitors. Several potent inhibitors of the BRD9 BD have recently been discovered, with anticancer and anti‐inflammation activity. However, its paralogue, BRD7 BD, remains unexploited. Here, we identified new chemotypes targeting BRD7 BD by using NMR fragment‐based screening. BRD7/9 BDs exhibit similar patterns of chemical‐shift perturbation upon the titration of hit compound 1. The crystal structure revealed that 1 repels the Y222 group of BRD9 BD in a similar way to that for butyryllysine, but not acetyllysine and known inhibitors. Hit 1 induced less rearrangement of residue F161 of BRD9 BD than acetyllysine, butyryllysine, and crotonyllysine. Our study provides structural insight into a new generation of butyryllysine mimics for probing the function of BRD7/9 BD.