Bortezomib

Bortezomib, sold under the brand name Velcade among others, is an anti-cancer medication used to treat multiple myeloma and mantle cell lymphoma.^[1] This includes multiple myeloma in those who have and have not previously received treatment. It is generally used together with other medications.^[2] See also Bortezomib.

Bortezomib is an N-protected dipeptide and can be written as Pyz-Phe-boroLeu, which stands for pyrazinoic acid, phenylalanine and Leucine with a boronic acid instead of a carboxylic acid.

The boron atom in bortezomib binds the catalytic site of the 20S proteasome^[3] with high affinity and specificity.

• 20S proteasome (2f16).
• 20S proteasome bound with 6 molecules of bortezomib.
• Bortezomib binding site. Interacting residues are labeled.
• The catalytic threonine residue is covalently bound to bortezomib and its activity is blocked.

In normal cells, the proteasome regulates protein expression and function by degradation of ubiquitylated proteins, and also rids the cell of abnormal or misfolded proteins. Clinical and preclinical data support a role for the proteasome in maintaining the immortal phenotype of myeloma cells, and cell-culture and xenograft data support a similar function in solid tumor cancers. While multiple mechanisms are likely to be involved, proteasome inhibition may prevent degradation of pro-apoptotic factors, thereby triggering programmed cell death in neoplastic cells. Recently, it was found that bortezomib caused a rapid and dramatic change in the levels of intracellular peptides that are produced by the proteasome.^[4] Some intracellular peptides have been shown to be biologically active, and so the effect of bortezomib on the levels of intracellular peptides may contribute to the biological and/or side effects of the drug.