2. Academic Validation
  3. Design, synthesis and anticancer evaluation of 3-methyl-1H-indazole derivatives as novel selective bromodomain-containing protein 4 inhibitors

Design, synthesis and anticancer evaluation of 3-methyl-1H-indazole derivatives as novel selective bromodomain-containing protein 4 inhibitors

  • Bioorg Med Chem. 2021 Dec 29;55:116592. doi: 10.1016/j.bmc.2021.116592.
Ru Dong 1,  Cheng Zhang 2,  Chao Wang 2,  Xin Zhou 1,  Wen Li 1,  Jin-Yang Zhang 1,  Min Wang 1,  Yong Xu 3,  Li-Ping Sun 4
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
  • 2 Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kai yuan Avenue, Guangzhou Science Park, Guangzhou, Guangdong 510530, China.
  • 3 Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kai yuan Avenue, Guangzhou Science Park, Guangzhou, Guangdong 510530, China. Electronic address: [email protected].
  • 4 Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: [email protected].
PMID: 34999525 DOI: 10.1016/j.bmc.2021.116592
Abstract

Bromodomain-containing Protein 4 (BRD4), an 'epigenetic reader', regulates chromatin structure and gene expression via recognizing and binding acetylated lysine in histones. BRD4 has become a therapeutic target for cancers because it promotes the expression of the tumor genes, such as c-Myc, NF-κB, and Bcl-2. In this study, a new series of 3-methyl-1H-indazole derivatives were designed via virtual screening and structure-based optimization. All compounds were synthesized and evaluated for their inhibitory activities to BRD4-BD1 and their antiproliferative effects in Cancer cell lines. Among them, several compounds (such as 9d, 9u and 9w) exhibited strong BRD4-BD1 affinities and inhibition activities, and potently suppressed MV4;11 Cancer cell line proliferation. Among them, compound 9d showed excellent selectivity for BRD4 and effectively suppressed c-Myc, the downstream protein of BRD4. This study provided new lead compounds for further biological evaluation on BRD4.

Keywords

Anticancer; BRD4 inhibitors; Pharmacophore; Virtual screening.

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