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, Hélène 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 C.S. Huang, Christopher J. Burns

Research output: Contribution to journalArticleResearchpeer-review

24 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1298-1303
Number of pages6
JournalACS Medicinal Chemistry Letters
Issue number12
Publication statusPublished - 14 Dec 2017
Externally publishedYes


  • benzodiazepine
  • Bromodomain
  • JQ1
  • leukemia
  • triazole

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