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Investigations on small molecule inhibitors targeting the histone H3K4 tri-methyllysine binding PHD-finger of JmjC histone demethylases
Bioorganic & Medicinal Chemistry ( IF 3.5 ) Pub Date : 2018-03-19 , DOI: 10.1016/j.bmc.2018.03.030
Bhaskar Bhushan 1 , Alexandre Erdmann 2 , Yijia Zhang 2 , Roman Belle 2 , Catrine Johannson 3 , Udo Oppermann 4 , Richard J Hopkinson 2 , Christopher J Schofield 2 , Akane Kawamura 1
Affiliation  

Plant homeodomain (PHD) containing proteins are important epigenetic regulators and are of interest as potential drug targets. Inspired by the amiodarone derivatives reported to inhibit the PHD finger 3 of KDM5A (KDM5A(PHD3)), a set of compounds were synthesised. Amiodarone and its derivatives were observed to weakly disrupt the interactions of a histone H3K4me3 peptide with KDM5A(PHD3). Selected amiodarone derivatives inhibited catalysis of KDM5A, but in a PHD-finger independent manner. Amiodarone derivatives also bind to H3K4me3-binding PHD-fingers from the KDM7 subfamily. Further work is required to develop potent and selective PHD finger inhibitors.



中文翻译:

靶向 JmjC 组蛋白去甲基化酶组蛋白 H3K4 三甲基赖氨酸结合 PHD 指的小分子抑制剂的研究

含有植物同源域 (PHD) 的蛋白质是重要的表观遗传调节因子,并且作为潜在的药物靶点是令人感兴趣的。受据报道可抑制 KDM5A 的 PHD 指 3 (KDM5A(PHD3)) 的胺碘酮衍生物的启发,合成了一组化合物。观察到胺碘酮及其衍生物弱破坏组蛋白 H3K4me3 肽与 KDM5A(PHD3) 的相互作用。选定的胺碘酮衍生物抑制 KDM5A 的催化,但以 PHD 指独立的方式。胺碘酮衍生物还与来自 KDM7 亚家族的 H3K4me3 结合 PHD 指结合。需要进一步的工作来开发有效和选择性的 PHD 手指抑制剂。

更新日期:2018-03-19
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