Targeting the proteasome pathway.
BACKGROUND
The ubiquitin-proteasome pathway functions as a main pathway in intracellular protein degradation and plays a vital role in almost all cellular events. Various inhibitors of this pathway have been developed for research purposes. The recent approval of bortezomib (PS-341, Velcade, a proteasome inhibitor, for the treatment of multiple myeloma has opened the way to the discovery of drugs targeting the proteasome and other components of the ubiquitin-proteasome pathway.


OBJECTIVE
We review the current understanding of the ubiquitin-proteasome pathway and inhibitors targeting this pathway, including proteasome inhibitors, as candidate drugs for chemical therapy.


METHODS
Preclinical and clinical data for inhibitors of the proteasome and the ubiquitin-proteasome pathway are discussed.


CONCLUSIONS
The proteasome and other members in the ubiquitin-proteasome pathway have emerged as novel therapeutic targets.
Tsukamoto
Sachiko
S
Chiba University, Graduate School of Science, 1-33 Yayoi-cho, Inage-ku, Chiba 263 8522, Japan.
Yokosawa
Hideyoshi
H
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001688:Biological Products / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use; D000069286:Bortezomib; D016503:Drug Delivery Systems; D055808:Drug Discovery; D006801:Humans; D007783:Lactones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000737:chemistry / Q000145:classification / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D025801:Ubiquitin / Q000502:physiology; D044764:Ubiquitin-Activating Enzymes / Q000037:antagonists & inhibitors; D014452:Ubiquitins / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D001688:Biological Products; D001897:Boronic Acids; D007783:Lactones; D010455:Peptides; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D011758:Pyrroles; D025801:Ubiquitin; D014452:Ubiquitins; C067713:lactacystin; D000069286:Bortezomib; C475865:marizomib; D046988:Proteasome Endopeptidase Complex; D044764:Ubiquitin-Activating Enzymes; D000111:Acetylcysteine