title: Proteasome inhibitors: an expanding army attacking a unique target.
abstract: Proteasomes are large, multisubunit proteolytic complexes presenting multiple targets for therapeutic intervention. The 26S proteasome consists of a 20S proteolytic core and one or two 19S regulatory particles. The 20S core contains three types of active sites. Many structurally diverse inhibitors of these active sites, both natural product and synthetic, have been discovered in the last two decades. One, bortezomib, is used clinically for treatment of multiple myeloma, mantle cell lymphoma, and acute allograft rejection. Five more recently developed proteasome inhibitors are in trials for treatment of myeloma and other cancers. Proteasome inhibitors also have activity in animal models of autoimmune and inflammatory diseases, reperfusion injury, promote bone and hair growth, and can potentially be used as anti-infectives. In addition, inhibitors of ATPases and deubiquitinases of 19S regulatory particles have been discovered in the last decade.
authors.affiliation: Department of Pharmacology and Toxicology, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH 03756, USA. alexei.f.kisselev@dartmouth.edu
authors.forename: Alexei F
authors.initials: AF
authors.lastname: Kisselev
authors.forename: Wouter A
authors.initials: WA
authors.lastname: van der Linden
authors.forename: Herman S
authors.initials: HS
authors.lastname: Overkleeft
mesh_terms: D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001897:Boronic Acids / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000069286:Bortezomib; D002986:Clinical Trials as Topic; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D009101:Multiple Myeloma / Q000188:drug therapy; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000627:therapeutic use
chemical_list: D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D001897:Boronic Acids; D007783:Lactones; D010456:Peptides, Cyclic; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex