Abstract
The ubiquitin-proteasome pathway (UPP) is an attractive chemotherapeutic target due to its intrinsically stringent regulation of cell cycle, pro-survival, and anti-apoptotic regulators that disproportionately favor survival and proliferation in malignant cells. A reversible first-in-class proteasome inhibitor, bortezomib, is Food and Drug Administration approved for multiple myeloma and relapsed/refractory mantle cell lymphoma and has proven to be extremely effective, both as a single agent and in combination. An irreversible second generation proteasome inhibitor, carfilzomib, has shown preclinical effectiveness against hematological and solid malignancies both in vitro and in vivo. Carfilzomib, a peptidylepoxyketone functions similarly to bortezomib through primary inhibition of chymotrypsin-like (ChT-L) activity at the β5 subunits of the core 20S proteasome. Carfilzomib is also currently achieving successful response rates within the clinical setting. In addition to conventional proteasome inhibitors, a novel approach may be to specifically target the hematological- specific immunoproteasome, thereby increasing overall effectiveness and reducing negative off-target effects. The immunoproteasome-specific inhibitor, IPSI-001, was shown to have inhibitory preference over the constitutive proteasome, and display enhanced efficiency of apoptotic induction of tumor cells from a hematologic origin. Herein, we discuss the preclinical and clinical development of carfilzomib and explore the potential of immunoproteasome-specific inhibitors, like IPSI-001, as a rational approach to exclusively target hematological malignancies.
Keywords: Ubiquitin proteasome pathway, proteasome inhibitors, carfilzomib, multiple myeloma
Current Cancer Drug Targets
Title: Second Generation Proteasome Inhibitors: Carfilzomib and Immunoproteasome-Specific Inhibitors (IPSIs)
Volume: 11 Issue: 3
Author(s): D. J. Kuhn, R. Z. Orlowski and C. C. Bjorklund
Affiliation:
Keywords: Ubiquitin proteasome pathway, proteasome inhibitors, carfilzomib, multiple myeloma
Abstract: The ubiquitin-proteasome pathway (UPP) is an attractive chemotherapeutic target due to its intrinsically stringent regulation of cell cycle, pro-survival, and anti-apoptotic regulators that disproportionately favor survival and proliferation in malignant cells. A reversible first-in-class proteasome inhibitor, bortezomib, is Food and Drug Administration approved for multiple myeloma and relapsed/refractory mantle cell lymphoma and has proven to be extremely effective, both as a single agent and in combination. An irreversible second generation proteasome inhibitor, carfilzomib, has shown preclinical effectiveness against hematological and solid malignancies both in vitro and in vivo. Carfilzomib, a peptidylepoxyketone functions similarly to bortezomib through primary inhibition of chymotrypsin-like (ChT-L) activity at the β5 subunits of the core 20S proteasome. Carfilzomib is also currently achieving successful response rates within the clinical setting. In addition to conventional proteasome inhibitors, a novel approach may be to specifically target the hematological- specific immunoproteasome, thereby increasing overall effectiveness and reducing negative off-target effects. The immunoproteasome-specific inhibitor, IPSI-001, was shown to have inhibitory preference over the constitutive proteasome, and display enhanced efficiency of apoptotic induction of tumor cells from a hematologic origin. Herein, we discuss the preclinical and clinical development of carfilzomib and explore the potential of immunoproteasome-specific inhibitors, like IPSI-001, as a rational approach to exclusively target hematological malignancies.
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Cite this article as:
J. Kuhn D., Z. Orlowski R. and C. Bjorklund C., Second Generation Proteasome Inhibitors: Carfilzomib and Immunoproteasome-Specific Inhibitors (IPSIs), Current Cancer Drug Targets 2011; 11 (3) . https://dx.doi.org/10.2174/156800911794519725
DOI https://dx.doi.org/10.2174/156800911794519725 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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