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.
Luyi Huang, Hui Li, Linli Li, Lu Niu, Raina Seupel, Chengyong Wu, Wei Cheng, Chong Chen, Bisen Ding, Paul E Brennan, Shengyong Yang
Author Information
Luyi Huang: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital , Sichuan University , Chengdu 610041 , P. R. China.
Hui Li: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital , Sichuan University , Chengdu 610041 , P. R. China.
Linli Li: 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.
Lu Niu: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital , Sichuan University , Chengdu 610041 , P. R. China.
Raina Seupel: Structural Genomics Consortium , University of Oxford , Old Road Campus Research Building, Roosevelt Drive , Oxford OX3 7DQ , U.K.
Chengyong Wu: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital , Sichuan University , Chengdu 610041 , P. R. China.
Wei Cheng: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital , Sichuan University , Chengdu 610041 , P. R. China.
Chong Chen: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital , Sichuan University , Chengdu 610041 , P. R. China.
Bisen Ding: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital , Sichuan University , Chengdu 610041 , P. R. China.
Paul E Brennan: Structural Genomics Consortium , University of Oxford , Old Road Campus Research Building, Roosevelt Drive , Oxford OX3 7DQ , U.K. ORCID
Shengyong Yang: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital , Sichuan University , Chengdu 610041 , P. R. China. ORCID
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 IC of 7 nM in homogeneous time-resolved fluorescence assay and a K 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.
