Selective inhibition of BET bromodomains

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, Michael R. McKeown, Yuchuan Wang, Amanda L. Christie, Nathan West, Michael J. Cameron, Brian Schwartz, Tom D. Heightman, Nicholas La Thangue, Christopher A. French, Olaf Wiest, Andrew L. Kung, Stefan Knapp () and James E. Bradner ()
Additional contact information
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
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
Stefan Knapp: Structural Genomics Consortium, 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

Nature, 2010, vol. 468, issue 7327, 1067-1073

Abstract: 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.

Date: 2010
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DOI: 10.1038/nature09504

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