Development of the proteasome inhibitor Velcade (Bortezomib)

Cancer Invest. 2004;22(2):304-11. doi: 10.1081/cnv-120030218.


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.

Publication types

  • Review

MeSH terms

  • Boronic Acids / pharmacokinetics
  • Boronic Acids / pharmacology*
  • Boronic Acids / therapeutic use
  • Bortezomib
  • Cell Survival
  • Clinical Trials as Topic
  • Cysteine Endopeptidases / pharmacology
  • Drug Design
  • Humans
  • Multienzyme Complexes / pharmacology
  • Neoplasms / drug therapy
  • Protease Inhibitors / pharmacokinetics
  • Protease Inhibitors / pharmacology*
  • Protease Inhibitors / therapeutic use
  • Proteasome Endopeptidase Complex
  • Pyrazines / pharmacokinetics
  • Pyrazines / pharmacology*
  • Pyrazines / therapeutic use
  • Ubiquitin-Activating Enzymes / pharmacology


  • Boronic Acids
  • Multienzyme Complexes
  • Protease Inhibitors
  • Pyrazines
  • Bortezomib
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex
  • Ubiquitin-Activating Enzymes