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Medicinal-Pharmaceutical Chemistry Commons

Open Access. Powered by Scholars. Published by Universities.®

2017

Australian Catholic University

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Full-Text Articles in Medicinal-Pharmaceutical Chemistry

Design, Synthesis, And Biological Activity Of 1,2,3-Triazolobenzodiazepine Bet Bromodomain Inhibitors [Accepted Manuscript], Phillip P. Sharp, Jean-Marc Garnier, Tamas Hatfaludi, Zhen Xu, David Segal, Kate E. Jarman, Hélène Jousset, Alexandra Garnham, John T. Feutrill, Anthony Cuzzupe, Peter Hall, Scott Taylor, Carl Walkley, Dean Tyler, Mark A. Dawson, Peter Czabotar, Andrew F. Wilks, Stefan Glaser, David C. S. Huang, Christopher J. Burns Jan 2017

Design, Synthesis, And Biological Activity Of 1,2,3-Triazolobenzodiazepine Bet Bromodomain Inhibitors [Accepted Manuscript], Phillip P. Sharp, Jean-Marc Garnier, Tamas Hatfaludi, Zhen Xu, David Segal, Kate E. Jarman, Hélène Jousset, Alexandra Garnham, John T. Feutrill, Anthony Cuzzupe, Peter Hall, Scott Taylor, Carl Walkley, Dean Tyler, Mark A. Dawson, Peter Czabotar, Andrew F. Wilks, Stefan Glaser, David C. S. Huang, Christopher J. Burns

Faculty of Health Sciences Publications

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.