Molecular basis of USP7 inhibition by selective small-molecule inhibitors

DOI: 10.1038/nature24451

Authors: Andrew Turnbull (CRUK Therapeutic Discovery Laboratories) , Stephanos Ioannidis (FORMA Therapeutics) , Wojciech W. Krajewski (CRUK Therapeutic Discovery Laboratories) , Adan Pinto-Fernandez (Target Discovery Institute, University of Oxford) , Claire Heride (University of Liverpool) , Agnes C. L. Martin (CRUK Therapeutic Discovery Laboratories) , Louise M. Tonkin (CRUK Therapeutic Discovery Laboratories) , Elizabeth C. Townsend (FORMA Therapeutics) , Shane M. Buker (FORMA Therapeutics) , David R. Lancia (FORMA Therapeutics) , Justin A. Caravella (FORMA Therapeutics) , Angela V. Toms (FORMA Therapeutics) , Thomas M. Charlton (Target Discovery Institute, University of Oxford) , Johanna Lahdenranta (FORMA Therapeutics) , Erik Wilker (FORMA Therapeutics) , Bruce C. Follows (FORMA Therapeutics) , Nicola J. Evans (CRUK Therapeutic Discovery Laboratories) , Lucy Stead (Institute of Translational Medicine, University of Liverpool) , Cristina Alli (CRUK Therapeutic Discovery Laboratories) , Vladislav V. Zarayskiy (FORMA Therapeutics) , Adam C. Talbot (FORMA Therapeutics) , Alexandre J. Buckmelter (FORMA Therapeutics) , Minghua Wang (FORMA Therapeutics) , Crystal L. Mckinnon (FORMA Therapeutics) , Fabienne Saab (CRUK Therapeutic Discovery Laboratories) , Joanna F. Mcgouran (Target Discovery Institute, University of Oxford) , Hannah Century (Target Discovery Institute, University of Oxford) , Malte Gersch (Medical Research Council Laboratory of Molecular Biology) , Marc S. Pittman (CRUK Therapeutic Discovery Laboratories) , C. Gary Marshall (FORMA Therapeutics) , Tony M. Raynham (CRUK Therapeutic Discovery Laboratories) , Mary Simcox (FORMA Therapeutics) , Lorna M. D. Stewart (CRUK Therapeutic Discovery Laboratories) , Sheila B. Mcloughlin (CRUK Therapeutic Discovery Laboratories) , Jaime A. Escobedo (FORMA Therapeutics) , Kenneth W. Bair (FORMA Therapeutics) , Christopher J. Dinsmore (FORMA Therapeutics) , Tim R. Hammonds (CRUK Therapeutic Discovery Laboratories) , Sunkyu Kim (FORMA Therapeutics) , Sylvie Urbé (University of Liverpool) , Michael J. Clague (University of Liverpool) , Benedikt M. Kessler (Target Discovery Institute, University of Oxford) , David Komander (Medical Research Council Laboratory of Molecular Biology)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Nature , VOL 12

State: Published (Approved)
Published: October 2017
Diamond Proposal Number(s): 15419 , 5070

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.

Journal Keywords: Drug discovery and development; Ubiquitylation; X-ray crystallography

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 16/11/2017 09:18

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)