Design, synthesis and biological evaluation of novel 6-phenyl-1, 3a, 4, 10b-tetrahydro-2H-benzo[c]thiazolo[4, 5-e]azepin-2-one derivatives as potential BRD4 inhibitors. Issue 15 (1st August 2020)

• Record Type: Journal Article
• Authors: Li, Qifei; Li, Jieming; Cai, Yan; Zou, Yuxing; Chen, Bin; Zou, Feng; Mo, Jiaxian; Han, Ting; Guo, Weiwei; Huang, Wenlong; Qiu, Qianqian; Qian, Hai
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 15(2020)
• Publication Date: 2020-08-01
• Subjects: BRD4 inhibitors -- Anti-tumor -- Apoptosis -- Anti-proliferation; 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.2020.115601
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Bromodomain-containing protein 4 (BRD4) is a key epigenetic regulator in cancer, and inhibitors targeting BRD4 exhibit great anticancer activity. By replacing the methyltriazole ring of the BRD4 inhibitor I-BET-762 with an N -methylthiazolidone heterocyclic ring, fifteen novel BRD4 inhibitors were designed and synthesized. Compound 13f had a hydrophobic acetylcyclopentanyl side chain, showing the most potent BRD4 inhibitory activity in the BRD4-BD1 inhibition assay (IC50 value of 110 nM), it also significantly suppressed the proliferation of MV-4-11 cells with high BRD4 level (IC50 value of 0.42 μM). Furthermore, the potent apoptosis-promoting and G0/G1 cycle-arresting activity of compound 13f were indicated by flow cytometry. As the downstream-protein of BRD4, c-Myc was in significantly low expression by compound 13f treatment in a dose-dependent manner. All the findings supported that this novel compound 13f provided a perspective for developing effective BRD4 inhibitors.