Design, Synthesis, and Biological Activity of 1,2,3-Triazolobenzodiazepine BET Bromodomain Inhibitors
Phillip P Sharp, Jean-Marc Garnier, Tamas Hatfaludi, Zhen Xu, David Segal, Kate E Jarman, Helene Jousset, Alexandra Garnham, John T Feutrill, Anthony Cuzzupe, Peter Hall, Scott Taylor, Carl R Walkley, Dean Tyler, Mark A Dawson, Peter Czabotar, Andrew F Wilks, Stefan Glaser, David CS Huang, Christopher J Burns
ACS MEDICINAL CHEMISTRY LETTERS | AMER CHEMICAL SOC | Published : 2017
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..View full abstract
Our work is supported by the NHMRC (fellowship to P.E.C.) and the Victorian State Government Operational Infrastructure Support, and the Australian Government NHMRC IRIISS.