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Discovery of a Chemical Tool Inhibitor Targeting the Bromodomains of TRIM24 and BRPF.
Bennett, James; Fedorov, Oleg; Tallant, Cynthia; Monteiro, Octovia; Meier, Julia; Gamble, Vicky; Savitsky, Pavel; Nunez-Alonso, Graciela A; Haendler, Bernard; Rogers, Catherine; Brennan, Paul E; Müller, Susanne; Knapp, Stefan.
Afiliación
  • Bennett J; The Structural Genomic Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, U.K.
  • Fedorov O; Target Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Headington, Oxford OX3 7FZ, U.K.
  • Tallant C; The Structural Genomic Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, U.K.
  • Monteiro O; Target Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Headington, Oxford OX3 7FZ, U.K.
  • Meier J; The Structural Genomic Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, U.K.
  • Gamble V; Target Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Headington, Oxford OX3 7FZ, U.K.
  • Savitsky P; The Structural Genomic Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, U.K.
  • Nunez-Alonso GA; Target Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Headington, Oxford OX3 7FZ, U.K.
  • Haendler B; Target Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Headington, Oxford OX3 7FZ, U.K.
  • Rogers C; Target Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Headington, Oxford OX3 7FZ, U.K.
  • Brennan PE; The Structural Genomic Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, U.K.
  • Müller S; Target Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Headington, Oxford OX3 7FZ, U.K.
  • Knapp S; The Structural Genomic Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, U.K.
J Med Chem ; 59(4): 1642-7, 2016 Feb 25.
Article en En | MEDLINE | ID: mdl-25974391
ABSTRACT
TRIM24 is a transcriptional regulator as well as an E3 ubiquitin ligase. It is overexpressed in diverse tumors, and high expression levels have been linked to poor prognosis in breast cancer patients. TRIM24 contains a PHD/bromodomain offering the opportunity to develop protein interaction inhibitors that target this protein interaction module. Here we identified potent acetyl-lysine mimetic benzimidazolones TRIM24 bromodomain inhibitors. The best compound of this series is a selective BRPF1B/TRIM24 dual inhibitor that bound with a KD of 137 and 222 nM, respectively, but exerted good selectivity over other bromodomains. Cellular activity of the inhibitor was demonstrated using FRAP assays as well as cell viability data.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Bencimidazoles / Proteínas Nucleares / Proteínas Portadoras / Proteínas Adaptadoras Transductoras de Señales Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2016 Tipo del documento: Article País de afiliación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Bencimidazoles / Proteínas Nucleares / Proteínas Portadoras / Proteínas Adaptadoras Transductoras de Señales Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2016 Tipo del documento: Article País de afiliación: Reino Unido