title: Exploring Selective Inhibition of the First Bromodomain of the Human Bromodomain and Extra-terminal Domain (BET) Proteins.
abstract: A midthroughput screening follow-up program targeting the first bromodomain of the human BRD4 protein, BRD4(BD1), identified an acetylated-mimic xanthine derivative inhibitor. This compound binds with an affinity in the low micromolar range yet exerts suitable unexpected selectivity in vitro against the other members of the bromodomain and extra-terminal domain (BET) family. A structure-based program pinpointed a role of the ZA loop, paving the way for the development of potent and selective BET-BRDi probes.
authors.affiliation: Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), UMR 7258; INSERM U1068; Institut Paoli-Calmettes; Aix-Marseille Université, UM105 , 13273 Marseille, France.
authors.forename: Brigitt
authors.initials: B
authors.lastname: Raux
authors.affiliation: Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), UMR 7258; INSERM U1068; Institut Paoli-Calmettes; Aix-Marseille Université, UM105 , 13273 Marseille, France.|Department of Organic Chemistry, Lobachevsky State University of Nizhni Novgorod , Gagarina av. 23, Nizhni Novgorod 603950, Russia.
authors.forename: Yuliia
authors.initials: Y
authors.lastname: Voitovich
authors.affiliation: Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), UMR 7258; INSERM U1068; Institut Paoli-Calmettes; Aix-Marseille Université, UM105 , 13273 Marseille, France.
authors.forename: Carine
authors.initials: C
authors.lastname: Derviaux
authors.affiliation: Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), UMR 7258; INSERM U1068; Institut Paoli-Calmettes; Aix-Marseille Université, UM105 , 13273 Marseille, France.
authors.forename: Adrien
authors.initials: A
authors.lastname: Lugari
authors.affiliation: Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), UMR 7258; INSERM U1068; Institut Paoli-Calmettes; Aix-Marseille Université, UM105 , 13273 Marseille, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Rebuffet
authors.affiliation: Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), UMR 7258; INSERM U1068; Institut Paoli-Calmettes; Aix-Marseille Université, UM105 , 13273 Marseille, France.|Screening Platform AD2P, CNRS, AFMB UMR 7257, Aix-Marseille Université , 13288 Marseille, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Milhas
authors.affiliation: Screening Platform AD2P, CNRS, AFMB UMR 7257, Aix-Marseille Université , 13288 Marseille, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Priet
authors.affiliation: Cisbio Bioassays, R&D , Parc Marcel Boiteux, BP 84175, 30200 Codolet, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Roux
authors.affiliation: Cisbio Bioassays, R&D , Parc Marcel Boiteux, BP 84175, 30200 Codolet, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Trinquet
authors.affiliation: Screening Platform AD2P, CNRS, AFMB UMR 7257, Aix-Marseille Université , 13288 Marseille, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Guillemot
authors.affiliation: Target Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Oxford OX3 7FZ, U.K.|Structural Genomics Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.|Goethe-University , Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Science, Campus Riedberg, Max-von Laue Str. 9, 60438 Frankfurt am Main, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.affiliation: Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), UMR 7258; INSERM U1068; Institut Paoli-Calmettes; Aix-Marseille Université, UM105 , 13273 Marseille, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Brunel
authors.affiliation: Department of Organic Chemistry, Lobachevsky State University of Nizhni Novgorod , Gagarina av. 23, Nizhni Novgorod 603950, Russia.
authors.forename: Alexey Yu
authors.initials: AY
authors.lastname: Fedorov
authors.affiliation: Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), UMR 7258; INSERM U1068; Institut Paoli-Calmettes; Aix-Marseille Université, UM105 , 13273 Marseille, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Collette
authors.affiliation: Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), UMR 7258; INSERM U1068; Institut Paoli-Calmettes; Aix-Marseille Université, UM105 , 13273 Marseille, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Roche
authors.affiliation: Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), UMR 7258; INSERM U1068; Institut Paoli-Calmettes; Aix-Marseille Université, UM105 , 13273 Marseille, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Betzi
authors.affiliation: Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), UMR 7258; INSERM U1068; Institut Paoli-Calmettes; Aix-Marseille Université, UM105 , 13273 Marseille, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Combes
authors.affiliation: Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), UMR 7258; INSERM U1068; Institut Paoli-Calmettes; Aix-Marseille Université, UM105 , 13273 Marseille, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Morelli
mesh_terms: D000107:Acetylation; D018797:Cell Cycle Proteins; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000187:drug effects; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D014970:Xanthines / Q000737:chemistry* / Q000494:pharmacology*; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D014970:Xanthines; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins