Design, synthesis and biological evaluation of novel 4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridine derivatives as potential BRD4 inhibitors.

Research paper by Xinzhou X Bi, Jieming J Li, Jiuhui J Li, Wei W Shi, Yuxuan Y Dai, Qifei Q Li, Wenjie W Zhang, Wenlong W Huang, Hai H Qian, Cheng C Jiang

Indexed on: 15 May '19Published on: 14 May '19Published in: Bioorganic & Medicinal Chemistry


Recently, diverse kinase inhibitors were reported having interaction with BRD4. It provided a strategy for developing a new structural framework for the next-generation BRD4-selective inhibitors. Starting from PLK1 kinase inhibitor BI-2536, we designed 18 compounds by modifying dihydropteridine core. Compound 23 showed potent BRD4 inhibitory activities with IC of 79 nM and no inhibitory activities for PLK1. Cell antiproliferation assay was performed and potent inhibitory activity against MV4;11 with IC of 1.53 μM. Cell apoptosis and western blotting indicated compound 23 induced apoptosis by down-regulating c-Myc. These novel selective BRD4 inhibitors provided new lead compounds for further drug development. Copyright © 2019 Elsevier Ltd. All rights reserved.