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.

摘要

含溴结构域蛋白 4 (BRD4) 通过两个溴结构域（BD1 和 BD2）结合组蛋白 N 末端尾部的乙酰化赖氨酸残基，以调节基因转录。抑制一个或两个溴结构域会导致不同的表型，表明 BD1 和 BD2 可能具有不同的功能。在这里，我们报告了天然产物 3',4',7,8-四羟基黄酮作为一种新型有效的选择性 BRD4 抑制剂的特征。该化合物对 BRD4-BD2 (IC50 = 204 nM) 的选择性比 BRD4-BD1 (IC ₅₀=17.9 µM)。共晶结构显示 3',4',7,8-四羟基黄酮与 BRD4-BD1 或 BRD4-BD2 的乙酰化赖氨酸结合口袋结合，但与 BRD4-BD2 的相互作用比 BRD4-BD1 多。我们的数据表明 3',4',7,8-四羟基黄酮是 BRD4-BD2 的有效选择性抑制剂，具有新型化学支架。鉴于其与当前 BRD4 抑制剂不同的化学结构，该化合物可以作为先导化合物为一类新型抗 BRD4 抑制剂打开大门。