Selective dual inhibitors of the cancer-related deubiquitylating proteases USP7 and USP47.
Open accessAbstract
Inhibitors of the cancer-related cysteine isopeptidase human ubiquitin-specific proteases 7 (USP7) and 47 (USP47) are considered to have potential as cancer therapeutics, owing to their ability to stabilize the tumor suppressor p53 and to decrease DNA polymerase β (Polβ), both of which are potential anticancer effects. A new class of dual small molecule inhibitors of these enzymes has been discovered. Compound 1, a selective inhibitor of USP7 and USP47 with moderate potency, demonstrates inhibition of USP7 in cells and induces elevated p53 and apoptosis in cancer cell lines. Compound 1 has been shown to demonstrate modest activity in human xenograft multiple myeloma and B-cell leukemia in vivo models. This activity may be the result of dual inhibition of USP7 and USP47. To address issues regarding potency and developability, analogues of compound 1 have been synthesized and tested, leading to improvements in potency, solubility, and metabolic reactivity profile. Further optimization is expected to yield preclinical candidates and, ultimately, clinical candidates for the treatment of multiple myeloma, prostate cancer, and other cancers.
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USP7 IC50 for P50429 and P22077 are in the low micromolar range.
“While the USP7 IC50 for P50429 and P22077 are in the low micromolar range, these inhibitors are not specific to USP7 as they also target the USP7 homolog USP47 (Tian et al., 2011; Weinstock et al., 2012).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Weinstock et al., 2012
P50429 and P22077 are not specific to USP7 as they also target USP47.
“While the USP7 IC50 for P50429 and P22077 are in the low micromolar range, these inhibitors are not specific to USP7 as they also target the USP7 homolog USP47 (Tian et al., 2011; Weinstock et al., 2012).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Weinstock et al., 2012
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- Authors
- Weinstock, J., Wu, J., Cao, P., Kingsbury, W. D., McDermott, J. L., Kodrasov, M. P., McKelvey, D. M., Suresh Kumar, K. G., Goldenberg, S. J., Mattern, M. R., & Nicholson, B.
- Affiliations
- Progenra (United States) (US)
- Progenra, Inc., 277 Great Valley Parkway, Malvern, Pennsylvania 19355, United States
- Corresponding author
- Nicholson, Benjamin
- Venue
- ACS Medicinal Chemistry Letters
- Publisher
- American Chemical Society (ACS)
- Published
- 2012-09-11
- Volume
- 3
- Issue
- 10
- Pages
- 789-792
- ISSN
- 1948-5875 (ISSN-L)
- PMC
- PMC4025646
- OpenAlex
- W2123095893
- Cited by
- 187
- References
- 18
- Citations by year
- 2026: 5 · 2025: 17 · 2024: 10 · 2023: 17 · 2022: 14 · 2021: 23 · 2020: 19 · 2019: 13 · 2018: 13 · 2017: 18 · 2016: 13 · 2015: 8 · 2014: 11 · 2013: 5 · 2012: 1
- FWCI
- 3.35
- 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)
- 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, USP47, deubiquitinase, dual enzyme inhibitors, small molecule inhibitors, p53 stabilization, DNA polymerase beta, apoptosis, multiple myeloma, B-cell leukemia, prostate cancer, drug development
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