Proteasome inhibitors: recent advances and new perspectives in medicinal chemistry.
The search for proteasome inhibitors began fifteen years ago. These inhibitors proved to be powerful tools for investigating many important cellular processes regulated by the ubiquitin-proteasome pathway. Targeting the proteasome pathway can also lead to new treatments for disorders like cancer, muscular dystrophies, inflammation and immune diseases. This is already true for cancer; the FDA approved bortezomib, a potent proteasome inhibitor, for treating multiple myeloma in 2003, and mantle cell lymphoma in 2006. The chemical structures identified in some of the early proteasome inhibitors have led to the development of new anti-cancer drugs (CEP-18770, Carfilzomib, NPI-0052). All these molecules are covalent bonding inhibitors that react with the catalytic Thr1-O(gamma) of the three types of active site. This review covers recent developments in medicinal chemistry of natural and synthetic proteasome inhibitors. Advances in non-covalent inhibitors that have no reactive group will be highlighted as they should minimize side-effects. New structures and new modes of action have been recently identified that open the door to new drug candidates for treating a range of diseases.
Genin
E
E
Chimie et photonique moléculaires, Université de Rennes 1, CNRS UMR 6510, bâtiment 10A, case 1012, Campus de Beaulieu, 35042 RENNES CEDEX, France.
Reboud-Ravaux
M
M
Vidal
J
J
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D015195:Drug Design; D006801:Humans; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex