基于结构的强效和选择性双溴结构域蛋白 4（BRD4）/丝氨酸苏氨酸激酶 1（PLK1）双重抑制剂的设计与开发。
Structure-Guided Design and Development of Potent and Selective Dual Bromodomain 4 (BRD4)/Polo-like Kinase 1 (PLK1) Inhibitors.
机构信息
Department of Chemistry , University of Massachusetts-Boston , Boston , Massachusetts 02125 , United States.
Phase I Clinical Trial Center & Department of Clinical Pharmacology, Xiangya Hospital , Central South University , Changsha , Hunan 410008 , P.R. China.
出版信息
J Med Chem. 2018 Sep 13;61(17):7785-7795. doi: 10.1021/acs.jmedchem.8b00765. Epub 2018 Aug 30.
Abstract
The simultaneous inhibition of polo-like kinase 1 (PLK1) and BRD4 bromodomain by a single molecule could lead to the development of an effective therapeutic strategy for a variety of diseases in which PLK1 and BRD4 are implicated. Compound 23 has been found to be a potent dual kinase-bromodomain inhibitor (BRD4-BD1 IC = 28 nM, PLK1 IC = 40 nM). Compound 6 was found to be the most selective PLK1 inhibitor over BRD4 in our series (BRD4-BD1 IC = 2579 nM, PLK1 IC = 9.9 nM). Molecular docking studies with 23 and BRD4-BD1/PLK1 as well as with 6 corroborate the biochemical assay results.
摘要
单一分子同时抑制 Polo 样激酶 1（PLK1）和 BRD4 溴结构域，可能为涉及 PLK1 和 BRD4 的多种疾病开发出有效的治疗策略。已发现化合物 23 是一种有效的双重激酶-溴结构域抑制剂（BRD4-BD1 IC = 28 nM，PLK1 IC = 40 nM）。在我们的系列中，化合物 6 被发现是对 BRD4 选择性最高的 PLK1 抑制剂（BRD4-BD1 IC = 2579 nM，PLK1 IC = 9.9 nM）。与 23 和 BRD4-BD1/PLK1 以及与 6 的分子对接研究证实了生化测定结果。
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