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.

• Antineoplastic agents
• Boronic acids
• Enzyme inhibitors (administration and dose)
• NF-κB (antagonists and inhibitors)
• Hematologic neoplasms (drug therapy)
• Multienzyme complexes (antagonists and inhibitors)

Abbreviations
MTD:	=	maximum tolerated dose
ICAM:	=	intracellular adhesion molecule
VCAM:	=	vascular cell adhesion molecule
IAP:	=	inhibitor of apoptosis
CLL:	=	chronic lymphocytic leukemia
CTEP:	=	Cancer Therapy Evaluation Program
BMSCs:	=	bone marrow stromal cells