机构：[1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital , Sichuan University , Chengdu 610041 , P. R. China.四川大学华西医院[2]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.[3]Structural Genomics Consortium , University of Oxford , Old Road Campus Research Building, Roosevelt Drive , Oxford OX3 7DQ , U.K.[4]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.
基金：
National Natural Science
Foundation of China (81573349, 81773633, and 21772130),
National Science and Technology Major Project
(2018ZX09711002-014-002, 2018ZX09711002-011-019,
2018ZX09201018, and 2018ZX09711003-003-006), and
1.3.5 project for disciplines of excellence, West China Hospital,
Sichuan University.
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2019]版：
大类|1 区医学
小类|1 区药物化学
最新[2023]版：
大类|1 区医学
小类|1 区药物化学
第一作者：
第一作者机构：[1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital , Sichuan University , Chengdu 610041 , P. R. China.
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Huang Luyi,Li Hui,Li Linli,et al.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.[J].Journal of medicinal chemistry.2019,62(9):4526-4542.doi:10.1021/acs.jmedchem.9b00096.
APA：
Huang Luyi,Li Hui,Li Linli,Niu Lu,Seupel Raina...&Yang Shengyong.(2019).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..Journal of medicinal chemistry,62,(9)
MLA：
Huang Luyi,et al."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.".Journal of medicinal chemistry 62..9(2019):4526-4542
医学