Discovery of the natural product 3', 4', 7, 8-tetrahydroxyflavone as a novel and potent selective BRD4 bromodomain 2 inhibitor. (1st January 2021)

• Record Type: Journal Article
• Authors: Li, Jiao; Zou, Wei; Yu, Koukou; Liu, Bing; Liang, Weifeng; Wang, Lisha; Lu, Yin; Jiang, Zequn; Wang, Aiyun; Zhu, Jiapeng
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 36:Number 1(2021)
• Page Start: 903
• Page End: 913
• Publication Date: 2021-01-01
• Subjects: Bromodomain-containing protein 4 -- natural product -- 3', 4', 7, 8-tetrahydroxyflavone -- inhibitor -- co-crystal structure; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2021.1906663
• Languages: English
• ISSNs: 1475-6366

Abstract

Abstract: Bromodomain-containing protein 4 (BRD4) binds acetylated lysine residues on the N-terminal tails of histones through two bromodomains (BD1 and BD2) to regulate gene transcription. Inhibiting one or both of bromodomains resulted in different phenotypes, suggesting BD1 and BD2 may have different functions. Here we report the characterisation of a natural product 3', 4', 7, 8-tetrahydroxyflavone as a novel and potent selective BRD4 inhibitor. The compound is 100-fold more selective for BRD4-BD2 (IC50 = 204 nM) than BRD4-BD1 (IC50 =17.9 µM). Co-crystal structures show 3', 4', 7, 8-tetrahydroxyflavone binds to the acetylated lysine binding pocket of BRD4-BD1 or BRD4-BD2, but establishes more interactions with BRD4-BD2 than BRD4-BD1. Our data suggest 3', 4', 7, 8-tetrahydroxyflavone as a potent selective inhibitor of BRD4-BD2 with a novel chemical scaffold. Given its distinct chemical structure from current BRD4 inhibitors, this compound may open the door for a novel class of anti-BRD4 inhibitors by serving as a lead compound. Graphical Abstract: UF0001