Novel proteasome inhibitors to overcome bortezomib resistance.

Abstract

The proteasome is an intracellular enzyme complex that degrades ubiquitin-tagged proteins and thereby regulates protein levels within the cell. Given this important role in maintaining cellular homeostasis, it is perhaps somewhat surprising that proteasome inhibitors have a therapeutic window. Proteasome inhibitors have demonstrated clinical efficacy in the treatment of multiple myeloma and mantle cell lymphoma and are under evaluation for the treatment of other malignancies. Bortezomib is the first and only Food and Drug Administration-approved proteasome inhibitor that inhibits this enzyme complex in a reversible fashion. Although bortezomib improves clinical outcomes when used as a single agent, most patients do not respond to this drug and those who do respond almost uniformly relapse. As such, efforts are underway to develop proteasome inhibitors that act through mechanisms distinct from that of bortezomib. Specifically, inhibitors that bind the active site of the proteasome and inhibit the complex irreversibly have been developed and are in advanced clinical trials. Inhibitors that act on sites of the proteasome outside of the catalytic center have also been identified and are in preclinical development. In this review, we discuss the structure and function of the proteasome. We then focus on the molecular biology, chemistry, and the preclinical and clinical efficacy of novel proteasome inhibitors as strategies to inhibit this target and overcome some forms of bortezomib resistance.

• Authors: Amy M Ruschak, Malik Slassi, Lewis E Kay, Aaron D Schimmer
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 103 Issue 13 Pg. 1007-17 (Jul 06 2011) ISSN: 1460-2105 [Electronic] United States
• PMID: 21606441 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• 5-amino-8-hydroxyquinoline
• Antineoplastic Agents
• Boronic Acids
• Hydroxyquinolines
• Lactones
• ONX 0912
• Oligopeptides
• Protease Inhibitors
• Proteasome Inhibitors
• Pyrazines
• Pyrroles
• Ubiquitinated Proteins
• Threonine
• Bortezomib
• delanzomib
• marizomib
• carfilzomib
• Clioquinol
• Chloroquine
• Proteasome Endopeptidase Complex

Topics

• Allosteric Site (drug effects)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Boronic Acids (pharmacology, therapeutic use)
• Bortezomib
• Cell Line, Tumor
• Chloroquine (pharmacology)
• Clioquinol (pharmacology)
• Drug Resistance, Neoplasm (drug effects)
• Humans
• Hydroxyquinolines (pharmacology)
• Lactones (pharmacology)
• Neoplasms (drug therapy, metabolism)
• Oligopeptides (pharmacology)
• Protease Inhibitors (pharmacology, therapeutic use)
• Proteasome Endopeptidase Complex (chemistry, metabolism)
• Proteasome Inhibitors
• Pyrazines (pharmacology, therapeutic use)
• Pyrroles (pharmacology)
• Threonine (analogs & derivatives, pharmacology)
• Ubiquitinated Proteins (metabolism)
• Ubiquitination (drug effects)