The 26S proteasome is a multifaceted target for anti-cancer therapies.

Abstract

Proteasomes play a critical role in the fate of proteins that are involved in major cellular processes, including signal transduction, gene expression, cell cycle, replication, differentiation, immune response, cellular response to stress, etc. In contrast to non-specific degradation by lysosomes, proteasomes are highly selective and destroy only the proteins that are covalently labelled with small proteins, called ubiquitins. Importantly, many diseases, including neurodegenerative diseases and cancers, are intimately connected to the activity of proteasomes making them an important pharmacological target. Currently, the vast majority of inhibitors are aimed at blunting the proteolytic activities of proteasomes. However, recent achievements in solving structures of proteasomes at very high resolution provided opportunities to design new classes of small molecules that target other physiologically-important enzymatic activities of proteasomes, including the de-ubiquitinating one. This review attempts to catalog the information available to date about novel classes of proteasome inhibitors that may have important pharmacological ramifications.

• Authors: Tatyana A Grigoreva, Vyacheslav G Tribulovich, Alexander V Garabadzhiu, Gerry Melino, Nickolai A Barlev
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 28 Pg. 24733-49 (Sep 22 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26295307 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Antineoplastic Agents
• Proteasome Inhibitors
• Proteasome Endopeptidase Complex
• ATP dependent 26S protease

Topics

• Animals
• Antineoplastic Agents (adverse effects, chemistry, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Drug Design
• Humans
• Molecular Structure
• Molecular Targeted Therapy (methods)
• Neoplasms (drug therapy, enzymology, pathology)
• Proteasome Endopeptidase Complex (drug effects, metabolism)
• Proteasome Inhibitors (adverse effects, chemistry, therapeutic use)
• Proteolysis
• Structure-Activity Relationship
• Ubiquitination