Journal article

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

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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Grants

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.