Discovery of specific inhibitors of human USP7/HAUSP deubiquitinating enzyme
Céline Reverdy1, Susan Conrath, Roman Lopez
1Hybrigenics Pharma, 3-5 Impasse Reille, 75014 Paris, France.
Abstract:
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.
Insights
Small-molecule inhibitors targeting USP7 (ubiquitin-specific protease 7) show promise for cancer therapy by regulating cancer cell growth and providing tools for deubiquitination research.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- The ubiquitin-specific protease 7 (USP7) enzyme regulates key proteins in cell cycle control, tumor suppression, and oncogenesis.
- USP7 is identified as a strategic therapeutic target for various cancers.
Purpose of the Study:
- To identify and characterize small-molecule antagonists of USP7.
- To evaluate the therapeutic potential of USP7 inhibitors in cancer treatment.
Main Methods:
- Biochemical assays and activity-based protein profiling were employed.
- USP7 inhibitor occupancy and selectivity were assessed in cancer cell lines.
- The mechanism of action involved covalent binding to the USP7 active site.
Main Results:
- Small-molecule USP7 inhibitors were successfully identified.
- These inhibitors demonstrated target engagement and selectivity in cancer cells.
- Inhibitors regulated USP7 substrate levels, mimicking USP7 knockdown effects like G1 cell cycle arrest in colon cancer.
Conclusions:
- USP7 inhibitors represent a potential therapeutic strategy for cancer treatment.
- The developed small molecules serve as valuable tools for studying deubiquitination processes.
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