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J Med Chem. 2019 May 9;62(9):4526-4542. doi: 10.1021/acs.jmedchem.9b00096. Epub 2019 Apr 30.

Discovery of Pyrrolo[3,2- d]pyrimidin-4-one Derivatives as a New Class of Potent and Cell-Active Inhibitors of P300/CBP-Associated Factor Bromodomain.

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State Key Laboratory of Biotherapy and Cancer Center, West China Hospital , Sichuan University , Chengdu 610041 , P. R. China.
Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy , Sichuan University , Sichuan 610041 , P. R. China.
Structural Genomics Consortium , University of Oxford , Old Road Campus Research Building, Roosevelt Drive , Oxford OX3 7DQ , U.K.
Target Discovery Institute , University of Oxford , NDM Research Building, Roosevelt Drive , Oxford OX3 7FZ , U.K.


Herein, we report the discovery of a series of new P300/CBP-associated factor (PCAF) bromodomain (BRD) inhibitors, which were obtained through a hit discovery process and subsequent structure-based optimization and structure-activity relationship analyses toward a retrieved hit compound (12). Among these inhibitors, ( R, R)-36n is the most potent one with an IC50 of 7 nM in homogeneous time-resolved fluorescence assay and a KD of 78 nM in isothermal titration calorimetry assay. This compound also exhibited activity against GCN5 and FALZ, but weak or no activity against other 29 BRD proteins and 422 kinases, indicating considerable selectivity. X-ray cocrystal structure analysis revealed the molecular interaction mode and the precise stereochemistry required for bioactivity. Cellular activity, preliminary RNA-seq analysis, and pharmacokinetic properties were also examined for this compound. Collectively, this study provides a versatile tool molecule to explore molecular mechanisms of PCAF BRD regulation and also offers a new lead compound for drug discovery targeting PCAF.

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