Chaikuad Apirat, Lang Steffen, Brennan Paul E, Temperini Claudia, Fedorov Oleg, Hollander Johan, Nachane Ruta, Abell Chris, Müller Susanne, Siegal Gregg, Knapp Stefan
Nuffield Department of Clinical Medicine, Structural Genomics Consortium and Target Discovery Institute, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, U.K.
Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, U.K.
J Med Chem. 2016 Feb 25;59(4):1648-53. doi: 10.1021/acs.jmedchem.5b01719. Epub 2016 Jan 13.
The P300/CBP-associated factor plays a central role in retroviral infection and cancer development, and the C-terminal bromodomain provides an opportunity for selective targeting. Here, we report several new classes of acetyl-lysine mimetic ligands ranging from mM to low micromolar affinity that were identified using fragment screening approaches. The binding modes of the most attractive fragments were determined using high resolution crystal structures providing chemical starting points and structural models for the development of potent and selective PCAF inhibitors.
P300/CBP相关因子在逆转录病毒感染和癌症发展中起核心作用，其C末端溴结构域为选择性靶向提供了机会。在此，我们报告了几类新的乙酰赖氨酸模拟配体，其亲和力范围从毫摩尔到低微摩尔，这些配体是通过片段筛选方法鉴定出来的。利用高分辨率晶体结构确定了最具吸引力片段的结合模式，为开发强效和选择性PCAF抑制剂提供了化学起始点和结构模型。
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