Bortezomib | Encyclopeptide

Chemical Identity

Property	Value
Chemical Formula	C19H25BN4O4
Molecular Weight	384.24 g/mol
CAS Number	179324-69-7
IUPAC Name	[(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic acid
Peptide Class	Proteasome Inhibitor (Dipeptide)
Sequence Homology	Synthetic dipeptide boronate

Structure

Bortezomib is a synthetic dipeptide boronic acid consisting of a pyrazine-2-carbonyl group, a phenylalanine residue, and a leucine bearing the boronic acid pharmacophore. The boronic acid moiety forms a reversible, covalent bond with the threonine residue in the active site of the 20S proteasome core. While technically a dipeptide rather than a traditional peptide drug, its peptide-like backbone connects it to peptide therapeutics.

Mechanism of Action

Bortezomib reversibly inhibits the 26S proteasome, a multi-catalytic enzyme complex responsible for ubiquitin-dependent protein degradation. By blocking the chymotrypsin-like activity of the 20S core, it causes accumulation of pro-apoptotic proteins (p53, Bax, IκBα) and prevents degradation of cell cycle regulators. Multiple myeloma cells are particularly sensitive due to their high protein synthesis rate and dependence on NF-κB survival signaling.

Clinical Applications

Bortezomib (Velcade) is approved for:

Multiple myeloma: First-line and relapsed/refractory treatment
Mantle cell lymphoma: Relapsed disease
First-line combination therapy: With dexamethasone and lenalidomide

In the APEX trial, bortezomib produced a 38% overall response rate in relapsed myeloma, establishing proteasome inhibition as a validated therapeutic strategy.

Pharmacokinetics

Half-life: 9-15 hours (first dose); 40-190 hours at steady state
Tmax: Subcutaneous 0.47-1.58 hours; intravenous 0.27-0.66 hours
Bioavailability: Subcutaneous bioavailability comparable to IV
Metabolism: Hepatic CYP3A4, CYP2C19, and CYP1A2
Route: Subcutaneous preferred over IV due to reduced peripheral neuropathy

Safety and Side Effects

Peripheral neuropathy (30-40%, dose-limiting), thrombocytopenia (28%), fatigue (26%), nausea (25%), and diarrhea (19%) are common. Herpes zoster reactivation risk necessitates antiviral prophylaxis. Bortezomib is pregnancy category D. Reversible upon discontinuation of therapy.

References

Richardson, P.G., et al. (2005). Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. New England Journal of Medicine, 352, 2487-2498.
Kane, R.C., et al. (2006). Bortezomib for the treatment of mantle cell lymphoma. Clinical Cancer Research, 12, 6239s-6243s.