IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v468y2010i7327d10.1038_nature09504.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/nature09504
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.
    File URL: https://libkey.io/10.1038/nature09504?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    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. Qing Bai & Enhua Shao & Denglei Ma & Binxuan Jiao & Seth D. Scheetz & Karen A. Hartnett-Scott & Vladimir A. Ilin & Elias Aizenman & Julia Kofler & Edward A. Burton, 2024. "A human Tau expressing zebrafish model of progressive supranuclear palsy identifies Brd4 as a regulator of microglial synaptic elimination," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    3. Laura Isigkeit & Espen Schallmayer & Romy Busch & Lorene Brunello & Amelie Menge & Lewis Elson & Susanne Müller & Stefan Knapp & Alexandra Stolz & Julian A. Marschner & Daniel Merk, 2024. "Chemogenomics for NR1 nuclear hormone receptors," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    4. 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.
    5. 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.
    6. 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.
    7. 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.
    8. Mengyu Liao & Xu Zhu & Yumei Lu & Xiaoping Yi & Youhui Hu & Yumeng Zhao & Zhisheng Ye & Xu Guo & Minghui Liang & Xin Jin & Hong Zhang & Xiaohong Wang & Ziming Zhao & Yupeng Chen & Hua Yan, 2024. "Multi-omics profiling of retinal pigment epithelium reveals enhancer-driven activation of RANK-NFATc1 signaling in traumatic proliferative vitreoretinopathy," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    9. 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.
    10. 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.
    11. 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.
    12. 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.
    13. Yuki Mori & Yoshino Akizuki & Rikuto Honda & Miyu Takao & Ayaka Tsuchimoto & Sota Hashimoto & Hiroaki Iio & Masakazu Kato & Ai Kaiho-Soma & Yasushi Saeki & Jun Hamazaki & Shigeo Murata & Toshikazu Ush, 2024. "Intrinsic signaling pathways modulate targeted protein degradation," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    14. 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.
    15. 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.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:468:y:2010:i:7327:d:10.1038_nature09504. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.