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.

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We thank the Diamond Light Source for access to beamlines I03 and I04. We thank S. M. Boyd for providing Extended Data Fig. 4, and S. Suhrawardy, V. Smith and Z. Yu for help with experiments. Work in the D.K. laboratory is supported by the Medical Research Council (U105192732), the European Research Council (309756), and the Lister Institute for Preventive Medicine. Work in the B.M.K. laboratory was supported by a John Fell Fund 133/075, the Wellcome Trust (097813/Z/11/Z) and the Engineering and Physical Sciences Research Council (EP/N034295/1). L.S. received a stipend from North West Cancer Research.

Author information

Author notes

    • Shane M. Buker
    • , Thomas M. Charlton
    • , Nicola J. Evans
    • , Joanna F. McGouran
    • , Hannah Century
    • , Marc S. Pittman
    • , Tony M. Raynham
    • , Mary Simcox
    •  & Kenneth W. Bair

    Present addresses: Goldfinch Bio, Cambridge, Massachusetts 02142, USA (S.M.B.); Department of Microbiology, University of Chicago, CLSC 1117, Chicago, Illinois 60637, USA (T.M.C.); Department of Chemistry, King’s College London, London SE1 1DB, UK (N.J.E.); Trinity College Dublin, College Green, Dublin 2, Ireland (J.F.M.); University College London, London WC1E 6BT, UK (H.C.); CRUK Centre for Drug Development, London EC1V 4AD, UK (M.S.P.); School of Health, Sport & Bioscience, University of East London, Stratford Campus, London E15 4LZ, UK (T.M.R.); Tarveda Therapeutics, Watertown, Massachusetts 02472, USA (M.S.); Athelas Therapeutics, Wellesley, Massachusetts 02482, USA (K.W.B.).

    • Andrew P. Turnbull
    • , Stephanos Ioannidis
    •  & Wojciech W. Krajewski

    These authors contributed equally to this work.


  1. CRUK Therapeutic Discovery Laboratories, London Bioscience Innovation Centre, London NW1 0NH, UK

    • Andrew P. Turnbull
    • , Wojciech W. Krajewski
    • , Nicola J. Evans
    • , Fabienne Saab
    • , Marc S. Pittman
    • , Tony M. Raynham
    • , Lorna M. D. Stewart
    •  & Tim R. Hammonds
  2. FORMA Therapeutics, Arsenal Street, Watertown, Massachusetts 02472, USA

    • Stephanos Ioannidis
    • , Elizabeth C. Townsend
    • , Shane M. Buker
    • , David R. Lancia
    • , Justin A. Caravella
    • , Angela V. Toms
    • , Johanna Lahdenranta
    • , Erik Wilker
    • , Bruce C. Follows
    • , Vladislav V. Zarayskiy
    • , Adam C. Talbot
    • , Alexandre J. Buckmelter
    • , Minghua Wang
    • , Crystal L. McKinnon
    • , C. Gary Marshall
    • , Mary Simcox
    • , Jaime A. Escobedo
    • , Kenneth W. Bair
    • , Christopher J. Dinsmore
    •  & Sunkyu Kim
  3. Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7FZ, UK

    • Adan Pinto-Fernandez
    • , Thomas M. Charlton
    • , Joanna F. McGouran
    • , Hannah Century
    •  & Benedikt M. Kessler
  4. Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown Street, Liverpool L69 3BX, UK

    • Claire Heride
    • , Lucy Stead
    • , Sylvie Urbé
    •  & Michael J. Clague
  5. CRUK Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge CB22 3AT, UK

    • Agnes C. L. Martin
    • , Louise M. Tonkin
    • , Cristina Alli
    •  & Sheila B. McLoughlin
  6. Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK

    • Malte Gersch
    •  & David Komander


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This study was directed by T.R.H., S.K., S.I., C.J.D., K.W.B., J.A.E., S.B.M., T.M.R., M.S., S.U., M.J.C., B.M.K. and D.K. S.I. led the chemistry, supported by C.J.D. and K.W.B. Synthetic routes and approaches were devised and carried out by B.C.F., A.C.T. and A.J.B., with computational chemistry support by D.R.L., J.A.C., M.W., C.L.M. and A.V.T. USP7 biochemical assays were developed and performed by C.L.M., A.C.L.M., L.M.T., C.A and F.S. USP10 and USP47 assays were performed by C.L.M. A.P.-F. carried out compound specificity studies and quantitative mass spectrometry using methods established by T.M.C., H.C. and J.F.M. under the guidance of B.M.K. Biophysical studies were performed as follows; surface plasmon resonance: A.C.L.M. and L.M.T.; circular dichroism: L.M.T.; kinact/Ki: A.C.L.M. using methods established by F.S. A.P.T. and W.W.K. performed the structural studies and analysis with input from D.R.L., A.V.T., N.J.E., M.G. and D.K. M.S.P. and L.M.T. produced protein for all experiments with input from L.M.D.S. Biological studies were designed and performed by C.H. with the help of L.S. under the guidance of S.U. and M.J.C., or performed independently by C.G.M., E.C.T., S.M.B., J.L., E.W. and M.S. under the guidance of S.I. and S.K. V.V.Z. carried out antiproliferative assay in MM.1S cells. J.L. and E.W. designed and supervised in vivo animal studies performed at Pharmaron, China. D.K., B.M.K., A.P.T. and S.I. wrote the manuscript, and all authors commented on the text. Authors S.I., C.J.D., T.R.H., S.K., S.U., M.J.C., B.M.K. and D.K. are current steering committee members of the DUB Alliance.

Competing interests

A.P.T., W.W.K., A.C.L.M., L.M.T., N.J.E., C.A., F.S., M.S.P., T.M.R., L.M.D.S., S.B.M. and T.R.H. are employees of CRUK Therapeutic Discovery Laboratories. S.I., E.C.T., S.M.B., D.R.L., J.A.C., A.V.T., J.L., E.W., B.C.F., V.V.Z., A.C.T., A.J.B., M.W., C.L.M., C.G.M., M.S., J.A.E., K.W.B., C.J.D. and S.K. are employees of FORMA Therapeutics. This work was performed by the DUB Alliance and funded by FORMA Therapeutics.

Corresponding authors

Correspondence to Andrew P. Turnbull or Stephanos Ioannidis or Benedikt M. Kessler or David Komander.

Reviewer Information Nature thanks W. Gu and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

PDF files

  1. 1.

    Reporting Summary

  2. 2.

    Supplementary Information

    This file contains chemical synthesis of USP7 compounds.

  3. 3.

    Supplementary Figure 1

    This file contains annotated full gel blots for all figures in the main manuscript.

Excel files

  1. 1.

    Supplementary Table 1

    This file contains DUBs identified by mass spectrometry after HA-UbC2Br labelling of MCF7 cell extracts.

  2. 2.

    Supplementary Table 2

    This file contains all proteins identified by mass spectrometry after HA-UbC2Br labelling of MCF7 cell extracts.

  3. 3.

    Supplementary Table 3

    This file contains the sequences for any RNAi/small RNA constructs used in this study.

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