Carfilzomib

Chemical Identity

Property	Value
Chemical Formula	C40H57N5O7
Molecular Weight	719.9 Da
CAS Number	868540-17-4
Peptide Class	Epoxyketone Tetrapeptide
Route	IV infusion

Structure

Carfilzomib (Kyprolis) is a tetrapeptide epoxyketone derived from the natural product epoxomicin. It contains a morpholine cap, a phenylalanine-homophenylalanine dipeptide, and a reactive epoxyketone warhead. The epoxyketone forms an irreversible dual covalent bond with the N-terminal threonine of the proteasome beta5 subunit.

Mechanism of Action

Carfilzomib irreversibly binds and inhibits the 20S proteasome beta5 subunit (chymotrypsin-like activity) through formation of a dual covalent morpholino adduct. Unlike bortezomib, the inhibition is irreversible, providing sustained proteasome blockade. It maintains activity in bortezomib-resistant cells.

Clinical Applications

• Multiple myeloma: Relapsed/refractory (Kyprolis)
• First-line myeloma: With dexamethasone +/- daratumumab
• Bortezomib-refractory disease: Active despite prior bortezomib
• Renal impairment: No dose adjustment required

Pharmacokinetics

• Half-life: 1 hour (rapid clearance)
• Metabolism: Peptidase cleavage and epoxide hydrolysis
• Elimination: Hepatic (primarily)
• Route: IV infusion (2-10 minutes on days 1, 2, 8, 9, 15, 16 of 28-day cycle)
• Protein binding: 97%

Safety and Side Effects

Cardiac failure (dose-limiting), hypertension, dyspnea, renal failure, fatigue, nausea, and peripheral neuropathy (lower than bortezomib). Requires cardiac monitoring and hydration.

References

• Dimopoulos, M.A., et al. (2012). ASPIRE trial: carfilzomib for multiple myeloma. New England Journal of Medicine, 367, 1397-1409.
• Siegel, D.S., et al. (2012). PX-171-003-A1: carfilzomib monotherapy. Clinical Cancer Research, 18, 4137-4146.