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

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.

SUBMITTER: Sharp PP

PROVIDER: S-EPMC5733269 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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

Sharp Phillip P PP Garnier Jean-Marc JM Hatfaludi Tamas T Xu Zhen Z Segal David D Jarman Kate E KE Jousset Hélène H Garnham Alexandra A Feutrill John T JT Cuzzupe Anthony A Hall Peter P Taylor Scott S Walkley Carl R CR Tyler Dean D Dawson Mark A MA Czabotar Peter P Wilks Andrew F AF Glaser Stefan S Huang David C S DCS Burns Christopher J CJ

ACS medicinal chemistry letters 20171114 12

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 bromo ...[more]

PMID: 29259751

Dataset Information

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

Publications

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

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