title: Discovery of a Chemical Tool Inhibitor Targeting the Bromodomains of TRIM24 and BRPF.
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.
authors.affiliation: The Structural Genomic Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, U.K.|Target Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Headington, Oxford OX3 7FZ, U.K.
authors.forename: James
authors.initials: J
authors.lastname: Bennett
authors.affiliation: The Structural Genomic Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, U.K.|Target Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Headington, Oxford OX3 7FZ, U.K.
authors.forename: Oleg
authors.initials: O
authors.lastname: Fedorov
authors.affiliation: The Structural Genomic Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, U.K.|Target Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Headington, Oxford OX3 7FZ, U.K.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Tallant
authors.affiliation: The Structural Genomic Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, U.K.|Target Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Headington, Oxford OX3 7FZ, U.K.
authors.forename: Octovia
authors.initials: O
authors.lastname: Monteiro
authors.affiliation: Target Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Headington, Oxford OX3 7FZ, U.K.
authors.forename: Julia
authors.initials: J
authors.lastname: Meier
authors.affiliation: Target Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Headington, Oxford OX3 7FZ, U.K.
authors.forename: Vicky
authors.initials: V
authors.lastname: Gamble
authors.affiliation: The Structural Genomic Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, U.K.|Target Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Headington, Oxford OX3 7FZ, U.K.
authors.forename: Pavel
authors.initials: P
authors.lastname: Savitsky
authors.affiliation: The Structural Genomic Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, U.K.|Target Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Headington, Oxford OX3 7FZ, U.K.
authors.forename: Graciela A
authors.initials: GA
authors.lastname: Nunez-Alonso
authors.affiliation: Global Drug Discovery, Bayer Pharma AG , Müllerstrasse 178, D-13353 Berlin, Germany.
authors.forename: Bernard
authors.initials: B
authors.lastname: Haendler
authors.affiliation: The Structural Genomic Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, U.K.|Target Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Headington, Oxford OX3 7FZ, U.K.
authors.forename: Catherine
authors.initials: C
authors.lastname: Rogers
authors.affiliation: The Structural Genomic Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, U.K.|Target Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Headington, Oxford OX3 7FZ, U.K.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Brennan
authors.affiliation: The Structural Genomic Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, U.K.|Target Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Headington, Oxford OX3 7FZ, U.K.
authors.forename: Susanne
authors.initials: S
authors.lastname: Müller
authors.affiliation: The Structural Genomic Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, U.K.|Target Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Headington, Oxford OX3 7FZ, U.K.|Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University , Max-von-Laue-Strasse 9 D-60438 Frankfurt am Main, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000187:drug effects; D000092468:Bromodomain Containing Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001562:Benzimidazoles; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D008239:Lysine; D009687:Nuclear Proteins; C086011:BRPF1 protein, human; D000092468:Bromodomain Containing Proteins; C555317:TRIM24 protein, human; C014353:benzimidazolone