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Bioorg Chem. 2016 Oct;68:236-44. doi: 10.1016/j.bioorg.2016.08.009. Epub 2016 Aug 24.

Design, synthesis and biological evaluation of dihydroquinoxalinone derivatives as BRD4 inhibitors.

Author information

1
Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
2
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
3
Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: jpzhou668@163.com.

Abstract

BRD4 plays a key role in transcriptional regulation. Recent biological and pharmacological studies have demonstrated that bromodomain-containing protein 4 (BRD4) is a viable drug target for cancer treatment. In this study, we synthesized a series of dihydroquinoxalinone derivatives and evaluated their BRD4 inhibitory activities, obtaining compound 5i with IC50 value of 73nM of binding activity in BRD4(1) and 258nM of cellular activity in MV-4-11 cancer cell lines. Docking studies were performed to explain the structure-activity relationship. Based on its potent biochemical and anti-proliferative activity, the novel BRD4 inhibitor compound 5i, is a promising lead compound for further investigation.

KEYWORDS:

BRD4 inhibitors; Cancer; Dihydroquinoxalinone derivatives; Molecular docking

PMID:
27580186
DOI:
10.1016/j.bioorg.2016.08.009
[Indexed for MEDLINE]

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