2. Academic Validation
  3. Discovery of a Chemical Tool Inhibitor Targeting the Bromodomains of TRIM24 and BRPF

Discovery of a Chemical Tool Inhibitor Targeting the Bromodomains of TRIM24 and BRPF

  • J Med Chem. 2016 Feb 25;59(4):1642-7. doi: 10.1021/acs.jmedchem.5b00458.
James Bennett 1 2,  Oleg Fedorov 1 2,  Cynthia Tallant 1 2,  Octovia Monteiro 1 2,  Julia Meier 2,  Vicky Gamble 2,  Pavel Savitsky 1 2,  Graciela A Nunez-Alonso 1 2,  Bernard Haendler 3,  Catherine Rogers 1 2,  Paul E Brennan 1 2,  Susanne Müller 1 2,  Stefan Knapp 1 2 4
Affiliations

Affiliations

  • 1 The Structural Genomic Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, U.K.
  • 2 Target Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Headington, Oxford OX3 7FZ, U.K.
  • 3 Global Drug Discovery, Bayer Pharma AG , Müllerstrasse 178, D-13353 Berlin, Germany.
  • 4 Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University , Max-von-Laue-Strasse 9 D-60438 Frankfurt am Main, Germany.
PMID: 25974391 DOI: 10.1021/acs.jmedchem.5b00458
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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