The 26S proteasome is a multifaceted target for anti-cancer therapies
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Tatyana A. Grigoreva1, Vyacheslav G. Tribulovich1, Alexander V. Garabadzhiu1, Gerry Melino1,2, Nickolai A. Barlev3
1St. Petersburg State Technological Institute (Technical University), St. Petersburng, Russia
2University of Rome Tor Vergata, Roma, Italy
3Institute of Cytology RAS, St. Petersburg, Russia
Nickolai A. Barlev, e-mail: [email protected]
Keywords: proteasome, proteasome inhibitors, ubiquitin-dependent proteolysis, combined anti-cancer therapy
Received: June 20, 2015 Accepted: July 10, 2015 Published: July 20, 2015
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.
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