Molecular basis of USP7 inhibition by selective small-molecule inhibitors.
Open accessAbstract
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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FT827 in complex with the USP7 catalytic domain enters the active site cleft and covalently modifies C223.
“Inhibitor FT827 in complex with the catalytic domain reveals that this inhibitor enters the active site cleft and covalently modifies C223.”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Turnbull et al., 2017
Many small molecule USP7 inhibitors have been found to inhibit cancer cell growth in vitro and in animal xenograft models.
“While human trials of USP7 inhibitors have yet to be conducted, many of these compounds have been found to inhibit cancer cell growth in vitro, as well as in animal xenograft models (Fan et al., 2013; Agathanggelou et al., 2017; Turnbull et al., 2017; Peng et al., 2019; Zhang et al., 2020).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Turnbull et al., 2017
FT671 in complex with the USP7 catalytic domain is several angstroms from C223, similar to XL188.
“The non-covalent inhibitor FT671 in complex with the catalytic domain reveals this inhibitor is several angstroms from C223, similar to XL188.”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Turnbull et al., 2017
Covalent modification of C223 by FT827 prevents C223 from acting as a nucleophile and hydrolyzing isopeptide bonds.
“This covalent modification of C223 prevents it from acting as a nucleophile and hydrolyzing isopeptide bonds (Turnbull et al., 2017).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Turnbull et al., 2017
Both USP7-FT inhibitor complexes reveal a misaligned catalytic triad and the switching loop in an unproductive conformation.
“Despite differences in binding, both USP7-FT inhibitor complexes reveal a misaligned catalytic triad and the switching loop being in an unproductive conformation.”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Turnbull et al., 2017
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- Authors
- Turnbull, A. P., Ioannidis, S., Krajewski, W. W., Pinto-Fernandez, A., Heride, C., Martin, A. C. L., Tonkin, L. M., Townsend, E. C., Buker, S. M., Lancia, D. R., Caravella, J. A., Toms, A. V., Charlton, T. M., Lahdenranta, J., Wilker, E., Follows, B. C., Evans, N. J., Stead, L., Alli, C., Zarayskiy, V. V., Talbot, A. C., Buckmelter, A. J., Wang, M., McKinnon, C. L., Saab, F., McGouran, J. F., Century, H., Gersch, M., Pittman, M. S., Marshall, C. G., Raynham, T. M., Simcox, M., Stewart, L. M. D., McLoughlin, S. B., Escobedo, J. A., Bair, K. W., Dinsmore, C. J., Hammonds, T. R., Kim, S., Urbé, S., Clague, M. J., Kessler, B. M., & Komander, D.
- Affiliations
- Cancer Research UK (GB)
- Forma Therapeutics (United States) (US)
- University of Liverpool (GB)
- University of Oxford (GB)
- MRC Laboratory of Molecular Biology (GB)
- Corresponding author
- Turnbull, Andrew P.
- Ioannidis, Stephanos
- Kessler, Benedikt M.
- Komander, David
- ORCID
- Turnbull, Andrew P.
- Heride, Claire
- Townsend, Elizabeth C.
- Buker, Shane M.
- Lancia, David R.
- Caravella, Justin A.
- Charlton, Thomas M.
- Lahdenranta, Johanna
- Wilker, Erik
- Evans, Nicola J.
- Stead, Lucy
- Wang, Minghua
- McGouran, Joanna F.
- Gersch, Malte
- Marshall, C. Gary
- Raynham, Tony M.
- Stewart, Lorna M. D.
- Dinsmore, Christopher J.
- Kim, Sunkyu
- Urbé, Sylvie
- Clague, Michael J.
- Kessler, Benedikt M.
- Komander, David
- Venue
- Nature
- Published
- 2017-10
- Volume
- 550
- Issue
- 7677
- Pages
- 481-486
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6029662
- OpenAlex
- W2766422151
- Cited by
- 463
- References
- 48
- Citations by year
- 2026: 51 · 2025: 64 · 2024: 51 · 2023: 48 · 2022: 47 · 2021: 63 · 2020: 56 · 2019: 38 · 2018: 40 · 2017: 4
- FWCI
- 15.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- UEL Research Repository (University of East London) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Arrow@dit (Dublin Institute of Technology) (submittedVersion, cc-by-nc-sa)
- RePEc: Research Papers in Economics (submittedVersion)
- Universitätsbibliographie, Universität Duisburg-Essen (submittedVersion)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
- Funders
- Wellcome Trust (097813/Z/11/Z)
- Engineering and Physical Sciences Research Council (EP/N034295/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- USP7, deubiquitinase inhibitors, MDM2 degradation, p53 reactivation, ubiquitination, protein stability, co-crystal structure, small molecule inhibitors, tumor growth inhibition, p21, cancer therapy
- MeSH terms
- Ubiquitin-Specific Peptidase 7, Animals, Apoenzymes, Female, Humans, Models, Molecular, Neoplasms, Piperidines, Pyrazoles, Pyrimidines, Substrate Specificity, Transcription, Genetic, Tumor Suppressor Protein p53, Crystallography, X-Ray, Xenograft Model Antitumor Assays, Cell Line, Tumor, Cell Proliferation, Mice, Proto-Oncogene Proteins c-mdm2, Ubiquitination
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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