The DOI matches its Crossref record; 45 of the 45 references it cites were found in a registry or an index.
Antitumor Activity of PR-171, a Novel Irreversible Inhibitor of the Proteasome
Open accessAbstract
Clinical studies with bortezomib have validated the proteasome as a therapeutic target for the treatment of multiple myeloma and non-Hodgkin's lymphoma. However, significant toxicities have restricted the intensity of bortezomib dosing. Here we describe the antitumor activity of PR-171, a novel epoxyketone-based irreversible proteasome inhibitor that is currently in clinical development. In comparison to bortezomib, PR-171 exhibits equal potency but greater selectivity for the chymotrypsin-like activity of the proteasome. In cell culture, PR-171 is more cytotoxic than bortezomib following brief treatments that mimic the in vivo pharmacokinetics of both molecules. Hematologic tumor cells exhibit the greatest sensitivity to brief exposure, whereas solid tumor cells and nontransformed cell types are less sensitive to such treatments. Cellular consequences of PR-171 treatment include the accumulation of proteasome substrates and induction of cell cycle arrest and/or apoptosis. Administration of PR-171 to animals results in the dose-dependent inhibition of the chymotrypsin-like proteasome activity in all tissues examined with the exception of the brain. PR-171 is well tolerated when administered for either 2 or 5 consecutive days at doses resulting in >80% proteasome inhibition in blood and most tissues. In human tumor xenograft models, PR-171 mediates an antitumor response that is both dose and schedule dependent. The antitumor efficacy of PR-171 delivered on 2 consecutive days is stronger than that of bortezomib administered on its clinical dosing schedule. These studies show the tolerability, efficacy, and dosing flexibility of PR-171 and provide validation for the clinical testing of PR-171 in the treatment of hematologic malignancies using dose-intensive schedules. [Cancer Res 2007;67(13):6383–91]
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Cites
β-catenin is a target for the ubiquitin–proteasome pathway
Aberle, H., Bauer, A., Stappert, J., Kispert, A., & Kemler, R. (1997) · The EMBO Journal · doi:10.1093/emboj/16.13.3797 · Cited by 2,529
Bortezomib or High-Dose Dexamethasone for Relapsed Multiple Myeloma
Richardson, P. G., Sonneveld, P., Schuster, M. W., Irwin, D., Stadtmauer, E. A., Facon, T., Harousseau, J.-L., Ben-Yehuda, D., Lonial, S., Goldschmidt, H., et al. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa043445 · Cited by 2,491
Hideshima, T., Richardson, P. G. G., Chauhan, D., Palombella, V. J., Elliott, P. J., Adams, J., & Anderson, K. C. (2001) · PubMed · Cited by 1,508
Proteasome inhibitors: a novel class of potent and effective antitumor agents.
Adams, J., Palombella, V. J., Sausville, E. A., Johnson, J. I., Destree, A. T., Lazarus, D. D., Maas, J., Pien, C. S., Prakash, S., & Elliott, P. J. (1999) · PubMed · Cited by 1,477
The proteasome: a suitable antineoplastic target
Adams, J. (2004) · Nature Reviews Cancer · doi:10.1038/nrc1361 · Cited by 1,201
Proteasome inhibitors: from research tools to drug candidates
Kisselev, A. F., & Goldberg, A. L. (2001) · Chemistry & Biology · doi:10.1016/s1074-5521(01)00056-4 · Cited by 1,184
Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells
Obeng, E. A., Carlson, L. M., Gutman, D. M., Harrington, W. J., Lee, K. P., & Boise, L. H. (2006) · Blood · doi:10.1182/blood-2005-08-3531 · Cited by 1,143
Proteolysis: from the lysosome to ubiquitin and the proteasome
Ciechanover, A. (2005) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1552 · Cited by 1,133
NF-κB as a Therapeutic Target in Multiple Myeloma
Hideshima, T., Chauhan, D., Richardson, P., Mitsiades, C., Mitsiades, N., Hayashi, T., Munshi, N., Dang, L., Castro, A., Palombella, V., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200360200 · Cited by 893
Orlowski, R. Z., Stinchcombe, T. E., Mitchell, B. S., Shea, T. C., Baldwin, A. S., Stahl, S., Adams, J., Esseltine, D.-L., Elliott, P. J., Pien, C. S., et al. (2002) · Journal of Clinical Oncology · doi:10.1200/jco.2002.01.133 · Cited by 760
Cited by
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
Radhakrishnan, S. K., Lee, C. S., Young, P., Beskow, A., Chan, J. Y., & Deshaies, R. J. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.02.029 · Cited by 526
Phenotypic screening in cancer drug discovery — past, present and future
Moffat, J. G., Rudolph, J., & Bailey, D. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4366 · Cited by 507
Drugging the undruggables: exploring the ubiquitin system for drug development
Huang, X., & Dixit, V. M. (2016) · Cell Research · doi:10.1038/cr.2016.31 · Cited by 427
Mechanisms of proteasome inhibitor action and resistance in cancer
McConkey, D. J., & Zhu, K. (2008) · Drug Resistance Updates · doi:10.1016/j.drup.2008.08.002 · Cited by 309
Metadata
- Authors
- Demo, S. D., Kirk, C. J., Aujay, M. A., Buchholz, T. J., Dajee, M., Ho, M. N., Jiang, J., Laidig, G. J., Lewis, E. R., Parlati, F., Shenk, K. D., Smyth, M. S., Sun, C. M., Vallone, M. K., Woo, T. M., Molineaux, C. J., & Bennett, M. K.
- Venue
- Cancer Research
- Published
- 2007-07-01
- Volume
- 67
- Issue
- 13
- Pages
- 6383-6391
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2126267349
- Cited by
- 678
- References
- 45
- FWCI
- 11.85
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Demo, S. D., Kirk, C. J., Aujay, M. A., Buchholz, T. J., Dajee, M., Ho, M. N., Jiang, J., Laidig, G. J., Lewis, E. R., Parlati, F., Shenk, K. D., Smyth, M. S., Sun, C. M., Vallone, M. K., Woo, T. M., Molineaux, C. J., & Bennett, M. K. (2007). Antitumor Activity of PR-171, a Novel Irreversible Inhibitor of the Proteasome. Cancer Research. https://doi.org/10.1158/0008-5472.can-06-4086
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
