Structure-guided development of a potent and selective non-covalent active-site inhibitor of USP7.
Open accessAbstract
Deubiquitinating enzymes (DUBs) have garnered significant attention as drug targets in the last 5-10 years. The excitement stems in large part from the powerful ability of DUB inhibitors to promote degradation of oncogenic proteins, especially proteins that are challenging to directly target but which are stabilized by DUB family members. Highly optimized and well-characterized DUB inhibitors have thus become highly sought after tools. Most reported DUB inhibitors, however, are polypharmacological agents possessing weak (micromolar) potency toward their primary target, limiting their utility in target validation and mechanism studies. Due to a lack of high-resolution DUB⋅small-molecule ligand complex structures, no structure-guided optimization efforts have been reported for a mammalian DUB. Here, we report a small-molecule⋅ubiquitin-specific protease (USP) family DUB co-structure and rapid design of potent and selective inhibitors of USP7 guided by the structure. Interestingly, the compounds are non-covalent active-site inhibitors.
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XL188 in complex with the USP7 catalytic domain binds about 5 Å from the catalytic triad.
“The inhibitor in complex with the USP7 catalytic domain reveals that binding occurs about 5 Å from the catalytic triad (Lamberto et al., 2017).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Lamberto et al., 2017
XL188 non-covalently binds the USP7 catalytic domain near the active site cleft.
“XL188 non-covalently binds the USP7 catalytic domain near the active site cleft.”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Lamberto et al., 2017
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USP7: Structure, substrate specificity, and inhibition
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Selective USP7 inhibition elicits cancer cell killing through a p53-dependent mechanism.
Schauer, N. J., Liu, X., Magin, R. S., Doherty, L. M., Chan, W. C., Ficarro, S. B., Hu, W., Roberts, R. M., Iacob, R. E., Stolte, B., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-62076-x · Cited by 125 · see citing works
Self-citationUSP7 Is a Master Regulator of Genome Stability
Valles, G. J., Bezsonova, I., Woodgate, R., & Ashton, N. W. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00717 · Cited by 114 · see citing works
“These phosphorylation events contribute to disrupting the p53-Mdm2 (Chehab et al., 2000; Shieh et al., 2000), and Mdm2-DAXX (Tang et al., 2013) interactions, as well as to the degradation of Mdm2 and Mdm4 (Stommel and Wahl, 2004; Chen et al., 2005; Pereg et al., 2005, 2006; LeBron et al., 2006).”
BackgroundIdentification and structure-guided development of pyrimidinone based USP7 inhibitors
O’Dowd, C. R., Helm, M. D., Rountree, J. S. S., Flasz, J. T., Arkoudis, E., Miel, H., Hewitt, P. R., Jordan, L., Barker, O., Hughes, C., et al. (2018) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.7b00512 · Cited by 71 · see citing works
Kinetic analysis of multistep USP7 mechanism shows critical role for target protein in activity.
Kim, R. Q., Geurink, P. P., Mulder, M. P. C., Fish, A., Ekkebus, R., El Oualid, F., van Dijk, W. J., van Dalen, D., Ovaa, H., van Ingen, H., et al. (2019) · Nature Communications · doi:10.1038/s41467-018-08231-5 · Cited by 41 · see citing works
Bashore, C., Jaishankar, P., Skelton, N. J., Fuhrmann, J., Hearn, B. R., Liu, P. S., Renslo, A. R., & Dueber, E. C. (2020) · ACS Chemical Biology · doi:10.1021/acschembio.0c00031 · Cited by 34 · see citing works
- Authors
- Lamberto, I., Liu, X., Seo, H.-S., Schauer, N. J., Iacob, R. E., Hu, W., Das, D., Mikhailova, T., Weisberg, E. L., Engen, J. R., Anderson, K. C., Chauhan, D., Dhe-Paganon, S., & Buhrlage, S. J.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Northeastern University (US)
- Harvard University (US)
- Corresponding author
- Buhrlage, Sara J.
- ORCID
- Venue
- Cell Chemical Biology
- Publisher
- Elsevier BV
- Published
- 2017-12
- Volume
- 24
- Issue
- 12
- Pages
- 1490-1500.e11
- ISSN
- 2451-9448 (ISSN-L)
- 2451-9456
- PMC
- PMC5749250
- OpenAlex
- W2765585400
- Cited by
- 192
- References
- 89
- Citations by year
- 2026: 15 · 2025: 26 · 2024: 17 · 2023: 16 · 2022: 21 · 2021: 26 · 2020: 35 · 2019: 20 · 2018: 14 · 2017: 2
- FWCI
- 8.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell chemical biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- NIGMS (P41 GM103403)
- NIH (R01 CA211681)
- Dana-Farber/Northeastern University Joint Program
- Ellison Foundation
- Chleck Family Foundation
- 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
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- USP7, deubiquitinase, DUB inhibitors, structure-based drug design, ubiquitin-specific protease, target validation
- MeSH terms
- Ubiquitin-Specific Peptidase 7, Dose-Response Relationship, Drug, Humans, Models, Molecular, Protease Inhibitors, Structure-Activity Relationship, Substrate Specificity, Thiophenes, Drug Design, Molecular Structure, Catalytic Domain, Ubiquitin
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