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Selective inhibition of BET bromodomains

Author

Listed:
  • Panagis Filippakopoulos

    (Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK)

  • Jun Qi

    (Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA)

  • Sarah Picaud

    (Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK)

  • Yao Shen

    (University of Notre Dame)

  • William B. Smith

    (Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA)

  • Oleg Fedorov

    (Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK)

  • Elizabeth M. Morse

    (Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA)

  • Tracey Keates

    (Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK)

  • Tyler T. Hickman

    (Brigham & Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA)

  • Ildiko Felletar

    (Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK)

  • Martin Philpott

    (Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK)

  • Shonagh Munro

    (University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK)

  • Michael R. McKeown

    (Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA
    Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA)

  • Yuchuan Wang

    (Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA)

  • Amanda L. Christie

    (Lurie Family Imaging Center, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA)

  • Nathan West

    (Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA)

  • Michael J. Cameron

    (Brigham & Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA)

  • Brian Schwartz

    (Brigham & Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA)

  • Tom D. Heightman

    (Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK)

  • Nicholas La Thangue

    (University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK)

  • Christopher A. French

    (Brigham & Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA)

  • Olaf Wiest

    (University of Notre Dame)

  • Andrew L. Kung

    (Lurie Family Imaging Center, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA
    Dana-Farber Cancer Institute and Children’s Hospital, Boston, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA)

  • Stefan Knapp

    (Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK
    University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK)

  • James E. Bradner

    (Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA
    Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA)

Abstract

Epigenetic proteins are intently pursued targets in ligand discovery. So far, successful efforts have been limited to chromatin modifying enzymes, or so-called epigenetic ‘writers’ and ‘erasers’. Potent inhibitors of histone binding modules have not yet been described. Here we report a cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains. High potency and specificity towards a subset of human bromodomains is explained by co-crystal structures with bromodomain and extra-terminal (BET) family member BRD4, revealing excellent shape complementarity with the acetyl-lysine binding cavity. Recurrent translocation of BRD4 is observed in a genetically-defined, incurable subtype of human squamous carcinoma. Competitive binding by JQ1 displaces the BRD4 fusion oncoprotein from chromatin, prompting squamous differentiation and specific antiproliferative effects in BRD4-dependent cell lines and patient-derived xenograft models. These data establish proof-of-concept for targeting protein–protein interactions of epigenetic ‘readers’, and provide a versatile chemical scaffold for the development of chemical probes more broadly throughout the bromodomain family.

Suggested Citation

  • Panagis Filippakopoulos & Jun Qi & Sarah Picaud & Yao Shen & William B. Smith & Oleg Fedorov & Elizabeth M. Morse & Tracey Keates & Tyler T. Hickman & Ildiko Felletar & Martin Philpott & Shonagh Munro, 2010. "Selective inhibition of BET bromodomains," Nature, Nature, vol. 468(7327), pages 1067-1073, December.
    • Handle: RePEc:nat:nature:v:468:y:2010:i:7327:d:10.1038_nature09504
    DOI: 10.1038/nature09504
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