Sharp Phillip P, Garnier Jean-Marc, Hatfaludi Tamas, Xu Zhen, Segal David, Jarman Kate E, Jousset Hélène, Garnham Alexandra, Feutrill John T, Cuzzupe Anthony, Hall Peter, Taylor Scott, Walkley Carl R, Tyler Dean, Dawson Mark A, Czabotar Peter, Wilks Andrew F, Glaser Stefan, Huang David C S, Burns Christopher J
Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3010, Australia.
ACS Med Chem Lett. 2017 Nov 14;8(12):1298-1303. doi: 10.1021/acsmedchemlett.7b00389. eCollection 2017 Dec 14.
A number of diazepines are known to inhibit bromo- and extra-terminal domain (BET) proteins. Their BET inhibitory activity derives from the fusion of an acetyl-lysine mimetic heterocycle onto the diazepine framework. Herein we describe a straightforward, modular synthesis of novel 1,2,3-triazolobenzodiazepines and show that the 1,2,3-triazole acts as an effective acetyl-lysine mimetic heterocycle. Structure-based optimization of this series of compounds led to the development of potent BET bromodomain inhibitors with excellent activity against leukemic cells, concomitant with a reduction in c- expression. These novel benzodiazepines therefore represent a promising class of therapeutic BET inhibitors.
已知多种二氮杂䓬可抑制溴结构域和额外末端结构域（BET）蛋白。它们的BET抑制活性源于在二氮杂䓬骨架上融合了一个模拟乙酰赖氨酸的杂环。在此，我们描述了一种新型1,2,3 - 三唑并苯并二氮杂䓬的直接、模块化合成方法，并表明1,2,3 - 三唑可作为一种有效的模拟乙酰赖氨酸的杂环。基于结构对该系列化合物进行优化，从而开发出了对白血病细胞具有优异活性的强效BET溴结构域抑制剂，同时c - 表达降低。因此，这些新型苯并二氮杂䓬代表了一类有前景的治疗性BET抑制剂。
