The DOI matches its Crossref record; 6 of the 6 references it cites were found in a registry or an index.
Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma
Open accessAbstract
The proteasome has emerged as an important target for cancer therapy with the approval of bortezomib, a first-in-class, reversible proteasome inhibitor, for relapsed/refractory multiple myeloma (MM). However, many patients have disease that does not respond to bortezomib, whereas others develop resistance, suggesting the need for other inhibitors with enhanced activity. We therefore evaluated a novel, irreversible, epoxomicin-related proteasome inhibitor, carfilzomib. In models of MM, this agent potently bound and specifically inhibited the chymotrypsin-like proteasome and immunoproteasome activities, resulting in accumulation of ubiquitinated substrates. Carfilzomib induced a dose- and time-dependent inhibition of proliferation, ultimately leading to apoptosis. Programmed cell death was associated with activation of c-Jun-N-terminal kinase, mitochondrial membrane depolarization, release of cytochrome c, and activation of both intrinsic and extrinsic caspase pathways. This agent also inhibited proliferation and activated apoptosis in patient-derived MM cells and neoplastic cells from patients with other hematologic malignancies. Importantly, carfilzomib showed increased efficacy compared with bortezomib and was active against bortezomib-resistant MM cell lines and samples from patients with clinical bortezomib resistance. Carfilzomib also overcame resistance to other conventional agents and acted synergistically with dexamethasone to enhance cell death. Taken together, these data provide a rationale for the clinical evaluation of carfilzomib in MM.
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Potent and selective inhibitors of the proteasome: Dipeptidyl boronic acids
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JNK promotes Bax translocation to mitochondria through phosphorylation of 14‐3‐3 proteins
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The role of ubiquitination in tumorigenesis and targeted drug discovery
Deng, L., Meng, T., Chen, L., Wei, W., & Wang, P. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-0107-0 · Cited by 744
Siegel, D. S., Martin, T., Wang, M., Vij, R., Jakubowiak, A. J., Lonial, S., Trudel, S., Kukreti, V., Bahlis, N., Alsina, M., et al. (2012) · Blood · doi:10.1182/blood-2012-05-425934 · Cited by 657
Self-citationTargeted Covalent Inhibitors for Drug Design
Baillie, T. A. (2016) · Angewandte Chemie International Edition · doi:10.1002/anie.201601091 · Cited by 578
Ubiquitin-like protein conjugation and the ubiquitin–proteasome system as drug targets
Bedford, L., Lowe, J., Dick, L. R., Mayer, R. J., & Brownell, J. E. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3321 · Cited by 563
Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma
Kumar, S., Kaufman, J. L., Gasparetto, C., Mikhael, J., Vij, R., Pegourie, B., Benboubker, L., Facon, T., Amiot, M., Moreau, P., et al. (2017) · Blood · doi:10.1182/blood-2017-06-788786 · Cited by 523
Metadata
- Authors
- Kuhn, D. J., Chen, Q., Voorhees, P. M., Strader, J. S., Shenk, K. D., Sun, C. M., Demo, S. D., Bennett, M. K., van Leeuwen, F. W. B., Chanan-Khan, A. A., & Orlowski, R. Z.
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2007-11-01
- Volume
- 110
- Issue
- 9
- Pages
- 3281-3290
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2016742872
- Cited by
- 768
- References
- 6
- FWCI
- 17.21
- Type
- journal article
- Language
- en
- Open access
- green
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- The paper
- Kuhn, D. J., Chen, Q., Voorhees, P. M., Strader, J. S., Shenk, K. D., Sun, C. M., Demo, S. D., Bennett, M. K., van Leeuwen, F. W. B., Chanan-Khan, A. A., & Orlowski, R. Z. (2007). Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood. https://doi.org/10.1182/blood-2007-01-065888
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