A chemical toolbox for the study of bromodomains and epigenetic signaling
A chemical toolbox for the study of bromodomains and epigenetic signaling
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DOI：
10.1038/s41467-019-09672-2
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发表时间：
2019-04-23
影响因子：
16.6
通讯作者：
Knapp, Stefan
中科院分区：
文献类型：
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作者：
Wu, Qin;Heidenreich, David;Knapp, Stefan
溴域(BRD)是保守的识别(读取)乙酰赖氨酸修饰的蛋白质相互作用模块，然而它们在调节细胞状态中的作用(S)以及它们作为靶向治疗策略发展的潜在靶点的了解很少。在这里，我们介绍了一组25个化学探针，选择性小分子抑制剂，覆盖29个人类溴域目标。我们使用BROMOcan全面评估了该探针集的选择性，并展示了该探针集识别BRD在细胞过程中的作用和潜在的翻译应用的实用性。例如，我们发现组蛋白乙酰化和糖酵解途径之间的串扰导致乳腺癌细胞株在葡萄糖剥夺或GLUT1抑制条件下对BRPF2/3 BRD抑制的脆弱性。该化学探针集将作为未来在发现溴域蛋白在正常和疾病状态下的新的生理作用方面的资源，并作为溴域靶标验证的工具集。
Bromodomains (BRDs) are conserved protein interaction modules which recognize (read) acetyl-lysine modifications, however their role(s) in regulating cellular states and their potential as targets for the development of targeted treatment strategies is poorly understood. Here we present a set of 25 chemical probes, selective small molecule inhibitors, covering 29 human bromodomain targets. We comprehensively evaluate the selectivity of this probe-set using BROMOscan and demonstrate the utility of the set identifying roles of BRDs in cellular processes and potential translational applications. For instance, we discovered crosstalk between histone acetylation and the glycolytic pathway resulting in a vulnerability of breast cancer cell lines under conditions of glucose deprivation or GLUT1 inhibition to inhibition of BRPF2/3 BRDs. This chemical probe-set will serve as a resource for future applications in the discovery of new physiological roles of bromodomain proteins in normal and disease states, and as a toolset for bromodomain target validation.