Journal article
Design, Synthesis, and Biological Activity of 1,2,3-Triazolobenzodiazepine BET Bromodomain Inhibitors
PP Sharp, JM Garnier, T Hatfaludi, Z Xu, D Segal, KE Jarman, H Jousset, A Garnham, JT Feutrill, A Cuzzupe, P Hall, S Taylor, CR Walkley, D Tyler, MA Dawson, P Czabotar, AF Wilks, S Glaser, DCS Huang, CJ Burns
ACS Medicinal Chemistry Letters | AMER CHEMICAL SOC | Published : 2017
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..
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Funding Acknowledgements
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.