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    Exploring Selective Inhibition of the First Bromodomain of the Human Bromodomain and Extra-terminal Domain (BET) Proteins
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    † 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
    § Screening Platform AD2P, CNRS, AFMB UMR 7257, Aix-Marseille Université, 13288 Marseille, France
    ∥ Cisbio Bioassays, R&D, Parc Marcel Boiteux, BP 84175, 30200 Codolet, France
    ⊥ 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
    *S.C. E-mail: [email protected]. Phone: (+33)491-835-551.
    *X.M. E-mail: [email protected]. Phone: (+33)486-977-331. Mailing address: Centre de Recherche en Cancérologie de Marseille (CRCM); INSERM U1068; CNRS UMR7258; Aix-Marseille Université UM105 & Institut Paoli Calmettes, 27 Boulevard Leï Roure CS30059, 13273 Marseille Cedex 9, France.
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2016, 59, 4, 1634–1641
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    https://doi.org/10.1021/acs.jmedchem.5b01708
    Published January 6, 2016
    Copyright © 2016 American Chemical Society
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    Abstract

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    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.

    Copyright © 2016 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.5b01708.

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    Accession Codes

    PDB codes for BRD4(BD1) with bound 1, 5 and 7, respectively, are 5EGU, 5EIS, and 5EI4.

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    Cite this: J. Med. Chem. 2016, 59, 4, 1634–1641
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    https://doi.org/10.1021/acs.jmedchem.5b01708
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