Discovery of small-molecule inhibitors of ubiquitin specific protease 7 (USP7) using integrated NMR and in silico techniques
Abstract
USP7 is a deubiquitinase implicated in destabilizing the tumor suppressor p53, and for this reason it has gained increasing attention as a potential oncology target for small molecule inhibitors. Herein we describe the biophysical, biochemical, and computational approaches that led to the identification of 4-(2-aminopyridin-3-yl)phenol compounds described by Kategaya ( Nature 2017 , 550 , 534 - 538 ) as specific inhibitors of USP7. Fragment based lead discovery (FBLD) by NMR combined with virtual screening and re-mining of biochemical high-throughput screening (HTS) hits led to the discovery of a series of ligands that bind in the "palm" region of the catalytic domain of USP7 and inhibit its catalytic activity. These ligands were then optimized by structure-based design to yield cell-active molecules with reasonable physical properties. This discovery process not only involved multiple techniques working in concert but also illustrated a unique way in which hits from orthogonal screening approaches complemented each other for lead identification.
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USP7 Inhibitor 2, part of the GNE-inhibitor screen, binds distal to the catalytic site.
“USP7 Inhibitor 2, which was part of the GNE-inhibitor screen, also binds distal to the catalytic site (Di Lello et al., 2017).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Di Lello et al., 2017
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USP7: Structure, substrate specificity, and inhibition
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USP7 Is a Master Regulator of Genome Stability
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- Authors
- Di Lello, P., Pastor, R., Murray, J. M., Blake, R. A., Cohen, F., Crawford, T. D., Drobnick, J., Drummond, J., Kategaya, L., Kleinheinz, T., Maurer, T., Rougé, L., Zhao, X., Wertz, I., Ndubaku, C., & Tsui, V.
- Affiliations
- Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
- Genentech (US)
- Corresponding author
- Pastor, Richard
- Tsui, Vickie
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2017-12-08
- Volume
- 60
- Issue
- 24
- Pages
- 10056-10070
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2768112882
- Cited by
- 90
- References
- 25
- Citations by year
- 2026: 6 · 2025: 18 · 2024: 11 · 2023: 9 · 2022: 12 · 2021: 11 · 2020: 12 · 2019: 4 · 2018: 7
- FWCI
- 2.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Energy
- U.S. Department of Health and Human Services (P41GM103393)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- USP7, deubiquitinase inhibitors, p53 stabilization, fragment-based drug discovery, NMR fragment screening, virtual screening, structure-based drug design, oncology drug targets
- MeSH terms
- Ubiquitin-Specific Peptidase 7, Aminopyridines, Binding Sites, Cell Line, Computer Simulation, Drug Evaluation, Preclinical, Enzyme Inhibitors, Humans, Magnetic Resonance Spectroscopy, Oxadiazoles, Crystallography, X-Ray, Catalytic Domain, Small Molecule Libraries, Drug Discovery
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