Second generation proteasome inhibitors: carfilzomib and immunoproteasome-specific inhibitors (IPSIs).

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 peptidyl-epoxyketone functions similarly to bortezomib through primary inhibition of chymotrypsin-like (ChT-L) activity at the b5 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.

• Authors: D J Kuhn, R Z Orlowski, C C Bjorklund
• Journal: Current cancer drug targets (Curr Cancer Drug Targets) Vol. 11 Issue 3 Pg. 285-95 (Mar 2011) ISSN: 1873-5576 [Electronic] Netherlands
• PMID: 21247387 (Publication Type: Journal Article, Review)

Chemical References

• Antineoplastic Agents
• Oligopeptides
• Protease Inhibitors
• Proteasome Inhibitors
• carfilzomib
• Proteasome Endopeptidase Complex

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Humans
• Neoplasms (drug therapy, immunology, metabolism)
• Oligopeptides (therapeutic use)
• Protease Inhibitors (therapeutic use)
• Proteasome Endopeptidase Complex (metabolism)
• Proteasome Inhibitors