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.

Research paper by Qifei Q Li, Jieming J Li, Yan Y Cai, Yuxing Y Zou, Bin B Chen, Feng F Zou, Jiaxian J Mo, Ting T Han, Weiwei W Guo, Wenlong W Huang, Qianqian Q Qiu, Hai H Qian

Indexed on: 08 Jul '20Published on: 08 Jul '20Published in: Bioorganic & Medicinal Chemistry


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 (IC value of 110 nM), it also significantly suppressed the proliferation of MV-4-11 cells with high BRD4 level (IC 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. Copyright © 2020 Elsevier Ltd. All rights reserved.