title: Development of the proteasome inhibitor Velcade (Bortezomib).
abstract: The dipeptide boronic acid analogue VELCADE (Bortezomib; formerly known as PS-341, LDP-341 and MLM341) is a potent and selective inhibitor of the proteasome, a multicatalytic enzyme that mediates many cellular regulatory signals by degrading regulatory proteins or their inhibitors. The proteasome is, thus, a potential target for pharmacological agents. Bortezomib, the first proteasome inhibitor to reach clinical trials, has shown in vitro and in vivo activity against a variety of malignancies, including myeloma, chronic lymphocytic leukemia, prostate cancer, pancreatic cancer, and colon cancer. The drug is rapidly cleared from the vascular compartment, but a novel pharmacodynamic assay has shown that bortezomib--mediated proteasome blockade is dose-dependent and reversible. Based on phase I studies demonstrating that bortezomib has manageable toxicities in patients with advanced cancers, phase II trials have been initiated for both solid and hematological malignancies.
authors.affiliation: Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, USA. julian.adams@ipi.com
authors.forename: Julian
authors.initials: J
authors.lastname: Adams
authors.forename: Michael
authors.initials: M
authors.lastname: Kauffman
mesh_terms: D001897:Boronic Acids / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000069286:Bortezomib; D002470:Cell Survival; D002986:Clinical Trials as Topic; D003546:Cysteine Endopeptidases / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D009097:Multienzyme Complexes / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy; D011480:Protease Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex; D011719:Pyrazines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D044764:Ubiquitin-Activating Enzymes / Q000494:pharmacology
chemical_list: D001897:Boronic Acids; D009097:Multienzyme Complexes; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D044764:Ubiquitin-Activating Enzymes