Molecular basis of USP7 inhibition by selective small-molecule inhibitors

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. Lancia, Justin A. Caravella, Angela V. Toms, Thomas M. Charlton, Johanna Lahdenranta, Erik Wilker, Bruce C. Follows, Nicola J. Evans, Lucy Stead, Cristina Alli, Vladislav V. Zarayskiy, Adam C. Talbot, Alexandre J. Buckmelter, Minghua Wang, Crystal L. McKinnon, Fabienne Saab, Joanna F. McGouran, Hannah Century, Malte Gersch, Marc S. Pittman, C. Gary Marshall, Tony M. Raynham, Mary Simcox, Lorna M. D. Stewart, Sheila B. McLoughlin, Jaime A. Escobedo, Kenneth W. Bair, Christopher J. Dinsmore, Tim R. Hammonds, Sunkyu Kim, Sylvie Urbé, Michael J. Clague, Benedikt M. Kessler () and David Komander ()
Additional contact information
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
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
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
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
Hannah Century: Target Discovery Institute, University of Oxford, Roosevelt Drive
Malte Gersch: Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue
Marc S. Pittman: CRUK Therapeutic Discovery Laboratories, London Bioscience Innovation Centre
C. Gary Marshall: FORMA Therapeutics, Arsenal Street
Tony M. Raynham: CRUK Therapeutic Discovery Laboratories, London Bioscience Innovation Centre
Mary Simcox: FORMA Therapeutics, Arsenal Street
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
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

Nature, 2017, vol. 550, issue 7677, 481-486

Abstract: 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.

Date: 2017
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DOI: 10.1038/nature24451

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