Design, synthesis, and biological activity of 1,2,3-Triazolobenzodiazepine BET Bromodomain inhibitors
- 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;
Publication Year 2017-12-14, Volume 8, Issue #12, Page 1298-1303
- Journal Title
- ACS Med Chem Lett
- Publication Type
- Journal Article
- 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.
- WEHI Research Division(s)
- Chemical Biology; Cancer And Haematology; Systems Biology And Personalised Medicine; Bioinformatics; Structural Biology
- PubMed ID
- Publisher's Version
- Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2018-01-15 12:39:46Last Modified: 2018-01-15 12:41:48