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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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    Cited by:

    1. Chun-Yi Cho & Patrick H. O’Farrell, 2023. "Stepwise modifications of transcriptional hubs link pioneer factor activity to a burst of transcription," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. John K. Barrows & Baicheng Lin & Colleen E. Quaas & George Fullbright & Elizabeth N. Wallace & David T. Long, 2022. "BRD4 promotes resection and homology-directed repair of DNA double-strand breaks," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    3. Sahar Harati & Lee A D Cooper & Josue D Moran & Felipe O Giuste & Yuhong Du & Andrei A Ivanov & Margaret A Johns & Fadlo R Khuri & Haian Fu & Carlos S Moreno, 2017. "MEDICI: Mining Essentiality Data to Identify Critical Interactions for Cancer Drug Target Discovery and Development," PLOS ONE, Public Library of Science, vol. 12(1), pages 1-18, January.
    4. Stella Amanda & Tze King Tan & Jolynn Zu Lin Ong & Madelaine Skolastika Theardy & Regina Wan Ju Wong & Xiao Zi Huang & Muhammad Zulfaqar Ali & Yan Li & Zhiyuan Gong & Hiroshi Inagaki & Ee Yong Foo & B, 2022. "IRF4 drives clonal evolution and lineage choice in a zebrafish model of T-cell lymphoma," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    5. Lorna A. Farrelly & Shuangping Zheng & Nadine Schrode & Aaron Topol & Natarajan V. Bhanu & Ryan M. Bastle & Aarthi Ramakrishnan & Jennifer C Chan & Bulent Cetin & Erin Flaherty & Li Shen & Kelly Gleas, 2022. "Chromatin profiling in human neurons reveals aberrant roles for histone acetylation and BET family proteins in schizophrenia," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    6. Ying Liang & Haiyue Xu & Tao Cheng & Yujuan Fu & Hanwei Huang & Wenchang Qian & Junyan Wang & Yuenan Zhou & Pengxu Qian & Yafei Yin & Pengfei Xu & Wei Zou & Baohui Chen, 2022. "Gene activation guided by nascent RNA-bound transcription factors," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    7. Andrew J. Tao & Jiewei Jiang & Gillian E. Gadbois & Pavitra Goyal & Bridget T. Boyle & Elizabeth J. Mumby & Samuel A. Myers & Justin G. English & Fleur M. Ferguson, 2023. "A biotin targeting chimera (BioTAC) system to map small molecule interactomes in situ," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    8. Alexandra D’Oto & Jie Fang & Hongjian Jin & Beisi Xu & Shivendra Singh & Anoushka Mullasseril & Victoria Jones & Ahmed Abu-Zaid & Xinyu Buttlar & Bailey Cooke & Dongli Hu & Jason Shohet & Andrew J. Mu, 2021. "KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    9. Jeannine Diesch & Marguerite-Marie Le Pannérer & René Winkler & Raquel Casquero & Matthias Muhar & Mark van der Garde & Michael Maher & Carolina Martínez Herráez & Joan J. Bech-Serra & Michaela Fellne, 2021. "Inhibition of CBP synergizes with the RNA-dependent mechanisms of Azacitidine by limiting protein synthesis," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    10. Victor Moreno & Maria Vieito & Juan Manuel Sepulveda & Vladimir Galvao & Tatiana Hernández-Guerrero & Bernard Doger & Omar Saavedra & Carmelo Carlo-Stella & Jean-Marie Michot & Antoine Italiano & Mass, 2023. "BET inhibitor trotabresib in heavily pretreated patients with solid tumors and diffuse large B-cell lymphomas," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    11. Mengxue Zhou & Jiaxin Wang & Jiaxing Pan & Hui Wang & Lujia Huang & Bo Hou & Yi Lai & Fengyang Wang & Qingxiang Guan & Feng Wang & Zhiai Xu & Haijun Yu, 2023. "Nanovesicles loaded with a TGF-β receptor 1 inhibitor overcome immune resistance to potentiate cancer immunotherapy," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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