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Design, synthesis, and biological activity of 1,2,3-triazolobenzodiazepine BET bromodomain inhibitors
Sharp, Phillip P. Garnier, Jean-Marc Hatfaludi, Tamas Xu, Zhen Segal, David Jarman, Kate E. Jousset, Hélène Garnham, Alexandra Feutrill, John T. Cuzzupe, Anthony
Sharp, Phillip P.
Garnier, Jean-Marc
Hatfaludi, Tamas
Xu, Zhen
Segal, David
Jarman, Kate E.
Jousset, Hélène
Garnham, Alexandra
Feutrill, John T.
Cuzzupe, Anthony
Author
Sharp, Phillip P.
Garnier, Jean-Marc
Hatfaludi, Tamas
Xu, Zhen
Segal, David
Jarman, Kate E.
Jousset, Hélène
Garnham, Alexandra
Feutrill, John T.
Cuzzupe, Anthony
Hall, Peter
Taylor, Scott
Walkley, Carl
Tyler, Dean
Dawson, Mark A.
Czabotar, Peter
Wilks, Andrew F.
Glaser, Stefan
Huang, David C. S.
Burns, Christopher J.
Garnier, Jean-Marc
Hatfaludi, Tamas
Xu, Zhen
Segal, David
Jarman, Kate E.
Jousset, Hélène
Garnham, Alexandra
Feutrill, John T.
Cuzzupe, Anthony
Hall, Peter
Taylor, Scott
Walkley, Carl
Tyler, Dean
Dawson, Mark A.
Czabotar, Peter
Wilks, Andrew F.
Glaser, Stefan
Huang, David C. S.
Burns, Christopher J.
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.
Keywords
benzodiazepine, Bromodomain, JQ1, leukemia, triazole
Date
2017
Type
Journal article
Journal
ACS Medicinal Chemistry Letters
Book
Volume
8
Issue
12
Page Range
1298-1303
Article Number
ACU Department
Mary MacKillop Institute for Health Research
Faculty of Health Sciences
Faculty of Health Sciences
Collections
Relation URI
Source URL
Event URL
Open Access Status
Published as green open access
License
File Access
Controlled
Open
Open