Second Generation Proteasome Inhibitors: Carfilzomib and Immunoproteasome-Specific Inhibitors (IPSIs)

Author(s): D. J. Kuhn, R. Z. Orlowski, C. C. Bjorklund.

Journal Name: Current Cancer Drug Targets

Volume 11 , Issue 3 , 2011

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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

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Article Details

VOLUME: 11
ISSUE: 3
Year: 2011
Page: [285 - 295]
Pages: 11
DOI: 10.2174/156800911794519725
Price: $58

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