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Molecular basis of USP7 inhibition by selective small-molecule inhibitors

Author

Listed:
  • Andrew P. Turnbull

    (CRUK Therapeutic Discovery Laboratories, London Bioscience Innovation Centre)

  • Stephanos Ioannidis

    (FORMA Therapeutics, Arsenal Street)

  • Wojciech W. Krajewski

    (CRUK Therapeutic Discovery Laboratories, London Bioscience Innovation Centre)

  • Adan Pinto-Fernandez

    (Target Discovery Institute, University of Oxford, Roosevelt Drive)

  • Claire Heride

    (Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool)

  • Agnes C. L. Martin

    (CRUK Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus)

  • Louise M. Tonkin

    (CRUK Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus)

  • Elizabeth C. Townsend

    (FORMA Therapeutics, Arsenal Street)

  • Shane M. Buker

    (FORMA Therapeutics, Arsenal Street
    Goldfinch Bio)

  • David R. Lancia

    (FORMA Therapeutics, Arsenal Street)

  • Justin A. Caravella

    (FORMA Therapeutics, Arsenal Street)

  • Angela V. Toms

    (FORMA Therapeutics, Arsenal Street)

  • Thomas M. Charlton

    (Target Discovery Institute, University of Oxford, Roosevelt Drive
    University of Chicago)

  • Johanna Lahdenranta

    (FORMA Therapeutics, Arsenal Street)

  • Erik Wilker

    (FORMA Therapeutics, Arsenal Street)

  • Bruce C. Follows

    (FORMA Therapeutics, Arsenal Street)

  • Nicola J. Evans

    (CRUK Therapeutic Discovery Laboratories, London Bioscience Innovation Centre
    King’s College London)

  • Lucy Stead

    (Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool)

  • Cristina Alli

    (CRUK Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus)

  • Vladislav V. Zarayskiy

    (FORMA Therapeutics, Arsenal Street)

  • Adam C. Talbot

    (FORMA Therapeutics, Arsenal Street)

  • Alexandre J. Buckmelter

    (FORMA Therapeutics, Arsenal Street)

  • Minghua Wang

    (FORMA Therapeutics, Arsenal Street)

  • Crystal L. McKinnon

    (FORMA Therapeutics, Arsenal Street)

  • Fabienne Saab

    (CRUK Therapeutic Discovery Laboratories, London Bioscience Innovation Centre)

  • Joanna F. McGouran

    (Target Discovery Institute, University of Oxford, Roosevelt Drive
    Trinity College Dublin)

  • Hannah Century

    (Target Discovery Institute, University of Oxford, Roosevelt Drive
    University College London)

  • Malte Gersch

    (Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue)

  • Marc S. Pittman

    (CRUK Therapeutic Discovery Laboratories, London Bioscience Innovation Centre
    CRUK Centre for Drug Development)

  • C. Gary Marshall

    (FORMA Therapeutics, Arsenal Street)

  • Tony M. Raynham

    (CRUK Therapeutic Discovery Laboratories, London Bioscience Innovation Centre
    University of East London)

  • Mary Simcox

    (FORMA Therapeutics, Arsenal Street
    Tarveda Therapeutics)

  • Lorna M. D. Stewart

    (CRUK Therapeutic Discovery Laboratories, London Bioscience Innovation Centre)

  • Sheila B. McLoughlin

    (CRUK Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus)

  • Jaime A. Escobedo

    (FORMA Therapeutics, Arsenal Street)

  • Kenneth W. Bair

    (FORMA Therapeutics, Arsenal Street
    Athelas Therapeutics)

  • Christopher J. Dinsmore

    (FORMA Therapeutics, Arsenal Street)

  • Tim R. Hammonds

    (CRUK Therapeutic Discovery Laboratories, London Bioscience Innovation Centre)

  • Sunkyu Kim

    (FORMA Therapeutics, Arsenal Street)

  • Sylvie Urbé

    (Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool)

  • Michael J. Clague

    (Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool)

  • Benedikt M. Kessler

    (Target Discovery Institute, University of Oxford, Roosevelt Drive)

  • David Komander

    (Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue)

Abstract

Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their inhibition can induce the degradation of selected proteins, potentially including otherwise ‘undruggable’ targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in various cancers. Here we report that two compounds, FT671 and FT827, inhibit USP7 with high affinity and specificity in vitro and within human cells. Co-crystal structures reveal that both compounds target a dynamic pocket near the catalytic centre of the auto-inhibited apo form of USP7, which differs from other USP deubiquitinases. Consistent with USP7 target engagement in cells, FT671 destabilizes USP7 substrates including MDM2, increases levels of p53, and results in the transcription of p53 target genes, induction of the tumour suppressor p21, and inhibition of tumour growth in mice.

Suggested Citation

  • Andrew P. Turnbull & Stephanos Ioannidis & Wojciech W. Krajewski & Adan Pinto-Fernandez & Claire Heride & Agnes C. L. Martin & Louise M. Tonkin & Elizabeth C. Townsend & Shane M. Buker & David R. Lanc, 2017. "Molecular basis of USP7 inhibition by selective small-molecule inhibitors," Nature, Nature, vol. 550(7677), pages 481-486, October.
    • Handle: RePEc:nat:nature:v:550:y:2017:i:7677:d:10.1038_nature24451
    DOI: 10.1038/nature24451
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    Citations

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    Cited by:

    1. Wai Cheung Chan & Xiaoxi Liu & Robert S. Magin & Nicholas M. Girardi & Scott B. Ficarro & Wanyi Hu & Maria I. Tarazona Guzman & Cara A. Starnbach & Alejandra Felix & Guillaume Adelmant & Anthony C. Va, 2023. "Accelerating inhibitor discovery for deubiquitinating enzymes," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Fredrik Trulsson & Vyacheslav Akimov & Mihaela Robu & Nila Overbeek & David Aureliano Pérez Berrocal & Rashmi G. Shah & Jürgen Cox & Girish M. Shah & Blagoy Blagoev & Alfred C. O. Vertegaal, 2022. "Deubiquitinating enzymes and the proteasome regulate preferential sets of ubiquitin substrates," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Christian Grethe & Mirko Schmidt & Gian-Marvin Kipka & Rachel O’Dea & Kai Gallant & Petra Janning & Malte Gersch, 2022. "Structural basis for specific inhibition of the deubiquitinase UCHL1," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    4. Zachary T. Spencer & Victoria H. Ng & Hassina Benchabane & Ghalia Saad Siddiqui & Deepesh Duwadi & Ben Maines & Jamal M. Bryant & Anna Schwarzkopf & Kai Yuan & Sara N. Kassel & Anant Mishra & Ashley P, 2023. "The USP46 deubiquitylase complex increases Wingless/Wnt signaling strength by stabilizing Arrow/LRP6," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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