Discovery of specific inhibitors of human USP7/HAUSP deubiquitinating enzyme.
Open accessAbstract
The human USP7 deubiquitinating enzyme was shown to regulate many proteins involved in the cell cycle, as well as tumor suppressors and oncogenes. Thus, USP7 offers a promising, strategic target for cancer therapy. Using biochemical assays and activity-based protein profiling in living systems, we identified small-molecule antagonists of USP7 and demonstrated USP7 inhibitor occupancy and selectivity in cancer cell lines. These compounds bind USP7 in the active site through a covalent mechanism. In cancer cells, these active-site-targeting inhibitors were shown to regulate the level of several USP7 substrates and thus recapitulated the USP7 knockdown phenotype that leads to G1 arrest in colon cancer cells. The data presented in this report provide proof of principle that USP7 inhibitors may be a valuable therapeutic for cancer. In addition, the discovery of such molecules offers interesting tools for studying deubiquitination.
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USP7 inhibitor HBX 19,818 specifically and covalently targets C223 with low micromolar affinity.
“USP7 inhibitor HBX 19,818 also specifically and covalently targets C223 with low micromolar affinity (Reverdy et al., 2012).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Reverdy et al., 2012
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- Authors
- Reverdy, C., Conrath, S., Lopez, R., Planquette, C., Atmanene, C., Collura, V., Harpon, J., Battaglia, V., Vivat, V., Sippl, W., & Colland, F.
- Affiliations
- Hybrigenics (France) (FR)
- Martin Luther University Halle-Wittenberg (DE)
- Corresponding author
- Colland, Frédéric
- Venue
- Chemistry & Biology
- Publisher
- Elsevier BV
- Published
- 2012-04
- Volume
- 19
- Issue
- 4
- Pages
- 467-477
- ISSN
- 1074-5521 (ISSN-L)
- OpenAlex
- W2076471871
- Cited by
- 270
- References
- 38
- Citations by year
- 2026: 12 · 2025: 17 · 2024: 14 · 2023: 10 · 2022: 16 · 2021: 23 · 2020: 28 · 2019: 21 · 2018: 19 · 2017: 33 · 2016: 22 · 2015: 13 · 2014: 23 · 2013: 15 · 2012: 4
- FWCI
- 7.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Chemistry & Biology (publishedVersion)
- PubMed (publishedVersion)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- USP7, deubiquitinase, small molecule inhibitors, covalent inhibitors, active site binding, cancer therapy, G1 cell cycle arrest, colon cancer, deubiquitination, activity-based protein profiling
- MeSH terms
- Ubiquitin-Specific Peptidase 7, Drug Evaluation, Preclinical, Enzyme Inhibitors, Humans, Apoptosis, Ubiquitin Thiolesterase, HCT116 Cells, Cell Line, Tumor, Small Molecule Libraries, G1 Phase Cell Cycle Checkpoints
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