| Literature DB >> 29259751 |
Phillip P Sharp1,2, Jean-Marc Garnier1,2, Tamas Hatfaludi1,2, Zhen Xu1,2, David Segal1,2, Kate E Jarman1,2, Hélène Jousset1,2, Alexandra Garnham1,2, John T Feutrill3, Anthony Cuzzupe3, Peter Hall1,2, Scott Taylor4, Carl R Walkley4, Dean Tyler5, Mark A Dawson5,6,7, Peter Czabotar1,2, Andrew F Wilks3, Stefan Glaser1,2, David C S Huang1,2, Christopher J Burns1,2,8.
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.Entities:
Year: 2017 PMID： 29259751 PMCID： PMC5733269 DOI： 10.1021/acsmedchemlett.7b00389
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345