Title: Design, Synthesis, and Biological Activity of 1,2,3-Triazolobenzodiazepine BET Bromodomain Inhibitors
Authors: 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
Issue Year: 2017
Series ACS Med. Chem. Lett.:
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.
URI: https://publications.svi.edu.au/publications/4772
Other Identifiers 10.1021/acsmedchemlett.7b00389
Publication type Article