2. Academic Validation
  3. Design, Synthesis, and Biological Activity of 1,2,3-Triazolobenzodiazepine BET Bromodomain Inhibitors

Design, Synthesis, and Biological Activity of 1,2,3-Triazolobenzodiazepine BET Bromodomain Inhibitors

  • ACS Med Chem Lett. 2017 Nov 14;8(12):1298-1303. doi: 10.1021/acsmedchemlett.7b00389.
Phillip P Sharp 1 2,  Jean-Marc Garnier 1 2,  Tamas Hatfaludi 1 2,  Zhen Xu 1 2,  David Segal 1 2,  Kate E Jarman 1 2,  Hélène Jousset 1 2,  Alexandra Garnham 1 2,  John T Feutrill 3,  Anthony Cuzzupe 3,  Peter Hall 1 2,  Scott Taylor 4,  Carl R Walkley 4,  Dean Tyler 5,  Mark A Dawson 5 6 7,  Peter Czabotar 1 2,  Andrew F Wilks 3,  Stefan Glaser 1 2,  David C S Huang 1 2,  Christopher J Burns 1 2 8
Affiliations

Affiliations

  • 1 Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
  • 2 Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • 3 Synthesis MedChem, 399 Royal Parade, Parkville, VIC 3052, Australia.
  • 4 St. Vincent's Institute of Medical Research and Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, VIC 3052, Australia.
  • 5 Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
  • 6 Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
  • 7 Sir Peter MacCallum Department of Oncology, The University of Melbourne, East Melbourne, VIC 3002, Australia.
  • 8 School of Chemistry, The Bio21 Institute, The University of Melbourne, Melbourne, VIC 3010, Australia.
PMID: 29259751 DOI: 10.1021/acsmedchemlett.7b00389
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 inhibitors.

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