Design, synthesis and evaluation of a novel BRD4 protein inhibitors
10.16438/j.0513-4870.2017-0407
- VernacularTitle:BRD4小分子抑制剂的设计、合成以及初步活性研究
- Author:
Jian-ping HU
1
;
Yan-lian LI
1
;
Huan-yu SHI
1
;
Bing XIONG
1
;
Jing-kang SHEN
1
Author Information
1. Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- Publication Type:ORIGINAL ARTICLES
- Keywords:
BRD4;
dihydroquinoxalin-2(1H)-one;
phenyl side chain
- From:
Acta Pharmaceutica Sinica
2017;52(10):1568-1577
- CountryChina
- Language:Chinese
-
Abstract:
Bromodomain-containing proteins (BCPs) can specifically recognize acetylated lysine (KAc) in histones and other substrate proteins. Recently, several kinase inhibitors were found to inhibit bromodomains, such as the PLK1 inhibitor BI-2536 and the JAK2 inhibitor TG101209, which bind to BRD4 with IC50 values of 25 nmol·L-1 and 130 nmol·L-1, respectively. To obtain potent BRD4 inhibitors from inhibitor BI-2536, we used dihydroquinoxalin-2(1H)-one to replace the 7,8-dihydropteridin-6(5H)-one in BI2536. By exploring the structure-activity relationships of the new dihydroquinoxalin-2(1H)-one structures, we obtained a novel phenyl side chain series of BRD4 inhibitors. We identified several potent BRD4 inhibitors, especially compounds 16, 22, 28 and 29, which had IC50 values below 100 nmol·L-1 in fluorescence anisotropy (FA) assays, indicating this series of compounds are worth to fruther investigation.
