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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; Hall, Peter; Taylor, Scott; Walkley, Carl R; Tyler, Dean; Dawson, Mark A; Czabotar, Peter; Wilks, Andrew F; Glaser, Stefan; Huang, David C S; Burns, Christopher J.
Afiliação
  • Sharp PP; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
  • Garnier JM; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • Hatfaludi T; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
  • Xu Z; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • Segal D; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
  • Jarman KE; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • Jousset H; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
  • Garnham A; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • Feutrill JT; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
  • Cuzzupe A; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • Hall P; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
  • Taylor S; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • Walkley CR; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
  • Tyler D; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • Dawson MA; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
  • Czabotar P; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • Wilks AF; Synthesis MedChem, 399 Royal Parade, Parkville, VIC 3052, Australia.
  • Glaser S; Synthesis MedChem, 399 Royal Parade, Parkville, VIC 3052, Australia.
  • Huang DCS; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
  • Burns CJ; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3010, Australia.
ACS Med Chem Lett ; 8(12): 1298-1303, 2017 Dec 14.
Article em En | MEDLINE | ID: mdl-29259751
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2017 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2017 Tipo de documento: Article