title: 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: St. Petersburg State Technological Institute (Technical University), St. Petersburg, Russia.
authors: Tatyana A
authors: TA
authors: Grigoreva
authors: St. Petersburg State Technological Institute (Technical University), St. Petersburg, Russia.
authors: Vyacheslav G
authors: VG
authors: Tribulovich
authors: St. Petersburg State Technological Institute (Technical University), St. Petersburg, Russia.
authors: Alexander V
authors: AV
authors: Garabadzhiu
authors: St. Petersburg State Technological Institute (Technical University), St. Petersburg, Russia.|University of Rome Tor Vergata, Roma, Italy.
authors: Gerry
authors: G
authors: Melino
authors: Institute of Cytology RAS, St. Petersburg, Russia.
authors: Nickolai A
authors: NA
authors: Barlev
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015195:Drug Design; D006801:Humans; D015394:Molecular Structure; D058990:Molecular Targeted Therapy / Q000379:methods*; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects* / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D059748:Proteolysis; D013329:Structure-Activity Relationship; D054875:Ubiquitination
chemical_list: D000970:Antineoplastic Agents; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease
keywords: combined anti-cancer therapy; proteasome; proteasome inhibitors; ubiquitin-dependent proteolysis