Identification and structure-guided development of pyrimidinone based USP7 inhibitors
Open accessAbstract
Ubiquitin specific protease 7 (USP7, HAUSP) has become an attractive target in drug discovery due to the role it plays in modulating Mdm2 levels and consequently p53. Increasing interest in USP7 is emerging due to its potential involvement in oncogenic pathways as well as possible roles in both metabolic and immune disorders in addition to viral infections. Potent, novel, and selective inhibitors of USP7 have been developed using both rational and structure-guided design enabled by high-resolution cocrystallography. Initial hits were identified via fragment-based screening, scaffold-hopping, and hybridization exercises. Two distinct subseries are described along with associated structure–activity relationship trends, as are initial efforts aimed at developing compounds suitable for in vivo experiments. Overall, these discoveries will enable further research into the wider biological role of USP7.
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Compound 46 binds a few angstroms from the active site residues of USP7.
“Similarly, the non-covalent pyrimidine-based USP7 inhibitor Compound 46 binds a few angstroms from the active site residues (O’Dowd et al., 2018).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as O’Dowd et al., 2018
Compound 46 is a non-covalent pyrimidine-based USP7 inhibitor.
“Similarly, the non-covalent pyrimidine-based USP7 inhibitor Compound 46 binds a few angstroms from the active site residues (O’Dowd et al., 2018).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as O’Dowd et al., 2018
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USP7: Structure, substrate specificity, and inhibition
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- Authors
- 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., Rozycka, E., Cassidy, E., McClelland, K., Odrzywol, E., Page, N., Feutren-Burton, S., Dvorkin, S., Gavory, G., & Harrison, T.
- Affiliations
- Almac Discovery Ltd., Centre for Precision Therapeutics, 97 Lisburn Road, Belfast, Northern Ireland BT9 7AE, United Kingdom
- Almac (United Kingdom) (GB)
- Queen's University Belfast (GB)
- ORCID
- Venue
- ACS Medicinal Chemistry Letters
- Publisher
- American Chemical Society (ACS)
- Published
- 2018-02-21
- Volume
- 9
- Issue
- 3
- Pages
- 238-243
- ISSN
- 1948-5875 (ISSN-L)
- PMC
- PMC5846043
- OpenAlex
- W2788145402
- Cited by
- 71
- References
- 22
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 7 · 2023: 4 · 2022: 11 · 2021: 7 · 2020: 12 · 2019: 6 · 2018: 3
- FWCI
- 2.67
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- ACS Medicinal Chemistry Letters (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (Queen's University Belfast) (acceptedVersion, other-oa)
- Funders
- European Regional Development Fund
- Almac Group
- Invest Northern Ireland (RD1010668)
- 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 › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- USP7, MDM2, p53, structure-based drug design, fragment screening, scaffold hopping, hybridization, structure-activity relationship, oncogenic signaling
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