Design, synthesis, and biological activity of 1,2,3-Triazolobenzodiazepine BET Bromodomain inhibitors

Author(s): Sharp, PP; GARNIER, JM; Hatfaludi, T; Xu, Z; Segal, D; Jarman, KE; Jousset, H; Garnham, A; Feutrill, JT; Cuzzupe, A; Hall, P; Taylor, S; Walkley, CR; Tyler, D; Dawson, MA; Czabotar, P; Wilks, AF; Glaser, S; Huang, DCS; Burns, CJ;
Details: Publication Year 2017-12-14,Volume 8,Issue #12,Page 1298-1303
Journal Title: ACS Med Chem Lett
Publication Type: Journal Article
Abstract: 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-MYC expression. These novel benzodiazepines therefore represent a promising class of therapeutic BET inhibitors.
Publisher: ACS
Research Division(s): Chemical Biology; Cancer And Haematology; Systems Biology And Personalised Medicine; Bioinformatics; Structural Biology
PubMed ID: 29259751
Publisher's Version: https://doi.org/10.1021/acsmedchemlett.7b00389
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2018-01-15 12:39:46

Last Modified: 2018-01-15 12:41:48