Design, synthesis and anticancer evaluation of 3-methyl-1H-indazole derivatives as novel selective bromodomain-containing protein 4 inhibitors. (1st February 2022)

• Record Type: Journal Article
• Authors: Dong, Ru; Zhang, Cheng; Wang, Chao; Zhou, Xin; Li, Wen; Zhang, Jin-Yang; Wang, Min; Xu, Yong; Sun, Li-Ping
• Is Part Of: Bioorganic & medicinal chemistry. Volume 55(2022)
• Publication Date: 2022-02-01
• Subjects: BRD4 inhibitors -- Virtual screening -- Anticancer -- Pharmacophore; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2021.116592
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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-1 H -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.