2. Academic Validation
  3. Discovery of a Bromodomain and Extra Terminal Domain (BET) Inhibitor with the Selectivity for the Second Bromodomain (BD2) and the Capacity for the Treatment of Inflammatory Diseases

Discovery of a Bromodomain and Extra Terminal Domain (BET) Inhibitor with the Selectivity for the Second Bromodomain (BD2) and the Capacity for the Treatment of Inflammatory Diseases

  • J Med Chem. 2023 Aug 10;66(15):10824-10848. doi: 10.1021/acs.jmedchem.3c01028.
Zhijie Wang 1,  Li Yin 2,  Zhenghan Xiong 2,  Fei Huang 1,  Na Yang 1,  Fei Jiang 1,  Huili Li 1,  Yong Cui 1,  Jiwei Ren 1,  Zitian Cheng 1,  Kun Jia 1,  Tao Lu 1 3,  Jiapeng Zhu 4,  Qinghua Hu 2,  Yadong Chen 1
Affiliations

Affiliations

  • 1 School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, P. R. China.
  • 2 School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, P. R. China.
  • 3 State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, P. R. 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, P. R. China.
PMID: 37478496 DOI: 10.1021/acs.jmedchem.3c01028
Abstract

Selective inhibitors targeting the first bromodomain (BD1) or the second bromodomain (BD2) of the bromodomain and extra terminal domain (BET) proteins have triggered extensive research to produce more specific agents. Herein, we described our efforts to design and synthesize a series of selective BET BD2 inhibitors with novel structures. Among them, compound 45 showed single-digit nanomolar potency against BRD4 BD2 (IC50: 1.6 nM) and a 328-fold selectivity for BRD4 BD2 over BRD4 BD1 (IC50: 524 nM). Besides, 45 possessed potent effects on regulating the differentiation of Th17 cells and reducing the levels of Th17-related cytokines by affecting the activation of STAT3 and NF-κB. Further studies demonstrated that 45 had significant therapeutic efficacy in mouse models of imiquimod (IMQ)-induced psoriasis and dextran sulfate sodium (DSS)-induced inflammatory bowel disease (IBD). This work provides a strong foundation for the development of selective BET BD2 inhibitors and the therapeutic strategy for psoriasis and IBD.

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