WestCHEM, Department of Pure and Applied Chemistry , University of Strathclyde, Thomas Graham Building , 295 Cathedral Street , Glasgow , G1 1XL , U.K.
J Med Chem. 2018 May 24;61(10):4317-4334. doi: 10.1021/acs.jmedchem.7b01666. Epub 2018 May 3.
The bromodomain and extra-terminal domain (BET) family of proteins bind acetylated lysine residues on histone proteins. The four BET bromodomains-BRD2, BRD3, BRD4, and BRDT-each contain two bromodomain modules. BET bromodomain inhibition is a potential therapy for various cancers and immunoinflammatory diseases, but few reported inhibitors show selectivity within the BET family. Inhibitors with selectivity for the first or second bromodomain are desired to aid investigation of the biological function of these domains. Focused library screening identified a series of tetrahydroquinoxalines with selectivity for the second bromodomains of the BET family (BD2). Structure-guided optimization of the template improved potency, selectivity, and physicochemical properties, culminating in potent BET inhibitors with BD2 selectivity.
溴结构域和末端结构域（BET）家族的蛋白与组蛋白上乙酰化的赖氨酸残基结合。四个 BET 溴结构域-BRD2、BRD3、BRD4 和 BRDT-每个都包含两个溴结构域模块。BET 溴结构域抑制是治疗各种癌症和免疫炎症性疾病的一种潜在疗法，但报道的几种抑制剂在 BET 家族内显示出选择性。具有对第一个或第二个溴结构域选择性的抑制剂，被期望有助于这些结构域的生物学功能的研究。有针对性的文库筛选确定了一系列具有 BET 家族（BD2）第二个溴结构域选择性的四氢喹喔啉。基于结构的模板优化提高了效力、选择性和物理化学性质，最终得到了具有 BD2 选择性的强效 BET 抑制剂。
