Carfilzomib

Kyprolis

Carfilzomib is a tetrapeptide epoxyketone that irreversibly inhibits the proteasome — the cell's protein-recycling machine. It is a good example of a peptide backbone weaponized with a reactive 'warhead': the epoxyketone group forms a stable covalent bond with the active site of the proteasome's chymotrypsin-like subunit, shutting it down. Because the binding is irreversible and highly selective for that subunit, carfilzomib is more targeted than the first-in-class proteasome inhibitor bortezomib, with a notably lower rate of the peripheral neuropathy that limits bortezomib. Proteasome inhibition is especially lethal to multiple myeloma cells. Myeloma is a cancer of plasma cells, which are professional antibody factories that produce enormous amounts of protein. This makes them unusually dependent on the proteasome and the associated stress-response systems to clear misfolded proteins. Blocking the proteasome causes toxic protein to accumulate, triggering the cancer cells' death (via the unfolded-protein response and apoptosis). Carfilzomib is approved, alone or in combination regimens, for relapsed or refractory multiple myeloma — patients whose disease has returned or resisted prior therapy. Carfilzomib is administered as an intravenous infusion in cycles by an oncology team, typically as part of combination regimens (for example with dexamethasone, or with lenalidomide and dexamethasone). Its most important safety considerations are cardiovascular and pulmonary: it can cause heart failure, high blood pressure, and other cardiac and pulmonary events, so patients are assessed and hydrated before treatment and monitored throughout. It was approved by the FDA in 2012 (Kyprolis). It is a hospital-administered anticancer medicine used strictly within specialist oncology care, not a general-purpose peptide.