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
  • 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.