An historic perspective of proteasome inhibition.
The ubiquitin-proteasome system (UPS) and associated signaling pathways are regarded today as an exciting area of development for novel therapeutics. However, two decades ago, following the discovery and elucidation of ubiquitin and the 26S proteasome as key mediators of protein turnover, the concept of inhibiting the UPS was not even considered a feasible therapeutic approach due to the assumption that inhibition of this pathway would have widespread deleterious effects. Subsequent clinical developments with the first-in-class proteasome inhibitor bortezomib have radically overturned that view, with the proteasome now recognized as a validated target and proteasome inhibition demonstrated to be a highly successful treatment for a number of hematologic malignancies. Here we provide a historic perspective on the emergence of proteasome inhibition, sharing some of the lessons learned along the way. We describe the development of bortezomib and the elucidation of the effects of its novel mechanism of action, and place the cutting-edge work described elsewhere in this issue in the context of these historic developments.
Oncology Clinical Research, Millennium Pharmaceuticals, Inc, Cambridge, MA 02139, USA. dixie-lee.esseltine@mpi.com
Dixie-Lee
DL
Esseltine
George
G
Mulligan
D000818:Animals; D000970:Antineoplastic Agents / Q000266:history* / Q000494:pharmacology / Q000627:therapeutic use; D001897:Boronic Acids / Q000266:history* / Q000494:pharmacology / Q000627:therapeutic use; D000069286:Bortezomib; D004354:Drug Screening Assays, Antitumor; D019337:Hematologic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D049673:History, 20th Century; D049674:History, 21st Century; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000266:history* / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000266:history* / Q000494:pharmacology / Q000627:therapeutic use; D011719:Pyrazines / Q000266:history* / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D025801:Ubiquitin / Q000037:antagonists & inhibitors / Q000266:history / Q000378:metabolism
D000970:Antineoplastic Agents; D001897:Boronic Acids; D061988:Proteasome Inhibitors; D011719:Pyrazines; D025801:Ubiquitin; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex