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

doi:10.1021/acsmedchemlett.7b00389

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. eCollection 2017 Dec 14.

Authors

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 Feutrill³, Anthony Cuzzupe³, Peter Hall^{1

2}, Scott Taylor⁴, Carl R Walkley⁴, Dean Tyler⁵, Mark A Dawson^{5

6

7}, Peter Czabotar^{1

2}, Andrew F Wilks³, 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.

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.