A small molecule inhibitor of ubiquitin-specific protease-7 induces apoptosis in multiple myeloma cells and overcomes bortezomib resistance.
Open accessAbstract
Bortezomib therapy has proven successful for the treatment of relapsed/refractory, relapsed, and newly diagnosed multiple myeloma (MM); however, dose-limiting toxicities and the development of resistance limit its long-term utility. Here, we show that P5091 is an inhibitor of deubiquitylating enzyme USP7, which induces apoptosis in MM cells resistant to conventional and bortezomib therapies. Biochemical and genetic studies show that blockade of HDM2 and p21 abrogates P5091-induced cytotoxicity. In animal tumor model studies, P5091 is well tolerated, inhibits tumor growth, and prolongs survival. Combining P5091 with lenalidomide, HDAC inhibitor SAHA, or dexamethasone triggers synergistic anti-MM activity. Our preclinical study therefore supports clinical evaluation of USP7 inhibitor, alone or in combination, as a potential MM therapy.
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USP7 nitrothiophene-based inhibitor 5091 is a promising therapeutic for treatment of multiple myeloma.
“USP7 nitrothiophene-based inhibitor 5091 proved to be a promising therapeutic for treatment of multiple myeloma (Chauhan et al., 2012)”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Chauhan et al., 2012
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- Authors
- Chauhan, D., Tian, Z., Nicholson, B., Kumar, K. G. S., Zhou, B., Carrasco, R., McDermott, J. L., Leach, C. A., Fulcinniti, M., Kodrasov, M. P., Weinstock, J., Kingsbury, W. D., Hideshima, T., Shah, P. K., Minvielle, S., Altun, M., Kessler, B. M., Orlowski, R., Richardson, P., Munshi, N., & Anderson, K. C.
- Affiliations
- Harvard University (US)
- Progenra (United States) (US)
- Chinese Academy of Sciences (CN)
- Karolinska Institutet (SE)
- University of Oxford (GB)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Chauhan, Dharminder
- Anderson, Kenneth C.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2012-09
- Volume
- 22
- Issue
- 3
- Pages
- 345-358
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC3478134
- OpenAlex
- W2082015682
- Cited by
- 589
- References
- 40
- Citations by year
- 2026: 22 · 2025: 42 · 2024: 35 · 2023: 44 · 2022: 35 · 2021: 59 · 2020: 72 · 2019: 47 · 2018: 43 · 2017: 46 · 2016: 46 · 2015: 27 · 2014: 39 · 2013: 29 · 2012: 2
- FWCI
- 12.59
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 375 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (P50100707, PO1-CA078378, R43CA115205, R43DK071391, VR-2011-2686)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- multiple myeloma, USP7 inhibitors, bortezomib resistance, apoptosis, deubiquitinase, MDM2, p21, lenalidomide, vorinostat, dexamethasone, combination therapy, small molecule inhibitors
- MeSH terms
- Bortezomib, Ubiquitin-Specific Peptidase 7, Lenalidomide, Animals, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Boronic Acids, Dexamethasone, Drug Therapy, Combination, Humans, Molecular Sequence Data, Multiple Myeloma, Neovascularization, Pathologic, Protease Inhibitors, Pyrazines, Random Allocation, Thalidomide, Thiophenes, Mice, SCID, Apoptosis, Drug Resistance, Neoplasm, Xenograft Model Antitumor Assays, Ubiquitin Thiolesterase, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p21, Mice, Proto-Oncogene Proteins c-mdm2
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