Discovery of Benzo[ cd]indol-2(1 H)-ones and Pyrrolo[4,3,2- de]quinolin-2(1 H)-ones as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the First Bromodomain with Potential High Efficiency against Acute Gouty Arthritis

  • J Med Chem. 2019 Dec 26;62(24):11080-11107. doi: 10.1021/acs.jmedchem.9b01010.
Fei Jiang  1  2 ,  Qinghua Hu  1 ,  Zhimin Zhang  1  3 ,  Hongmei Li  1  2 ,  Huili Li  1 ,  Dewei Zhang  1 ,  Hanwen Li  1 ,  Yu Ma  1 ,  Jingjing Xu  4 ,  Haifang Chen  1 ,  Yong Cui  1 ,  Yanle Zhi  1 ,  Yanmin Zhang  1 ,  Junyu Xu  1 ,  Jiapeng Zhu  4 ,  Tao Lu  1  2 ,  Yadong Chen  1  2
Affiliations
  • 1. School of Sciences , China Pharmaceutical University , 639 Longmian Avenue , Nanjing 211198 , P. R. China.
  • 2. State Key Laboratory of Natural Medicines , China Pharmaceutical University , 24 Tongjiaxiang , Nanjing 210009 , P. R. China.
  • 3. Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Institute of Materia Medica , Zhejiang Academy of Medical Sciences , Hangzhou 310013 , China.
  • 4. School of Medicine and Life Sciences, State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica , Nanjing University of Chinese Medicine , Nanjing 210023 , China.
PMID: 31789032 DOI: 10.1021/acs.jmedchem.9b01010
Abstract

The bromodomain and extra-terminal domain (BET) family of proteins are readers which specifically recognize histone-acetylated lysine residues. Each BET bromodomain protein contains two highly homologous domains: the first bromodomain (BD1) and the second bromodomain (BD2). Pan-BET bromodomain inhibition is a potential therapy for various cancers and immune-inflammatory diseases, but only few reported inhibitors show selectivity within the BET family. Herein, we identified a series of benzo[cd]indol-2(1H)-ones and pyrrolo[4,3,2-de]quinolin-2(1H)-ones with good selectivity for BET BD1. Through structure-based optimization, highly active and selective compounds are ultimately obtained. The representative compounds are the first reported inhibitors with selectivity more than 100-fold for BRD4(1) over BRD4(2). Among them, we further show that 68 (LT052) mediates BRD4/NF-κB/NLRP3 signaling inflammatory pathways with comparable protein expression and significantly improves symptoms of gout arthritis in a rat model. Therefore, selective pharmacological modulation of individual bromodomains could represent a strategy for the treatment of acute gouty arthritis.

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