Proteasome Inhibitor
A drug that blocks the proteasome — the cellular complex responsible for degrading damaged proteins. Proteasome inhibition causes toxic protein accumulation in cancer cells, triggering apoptosis. Bortezomib and carfilzomib are approved peptide-based proteasome inhibitors for multiple myeloma.
Technical Context
The 26S proteasome consists of a 20S core particle (barrel-shaped, contains catalytic sites with chymotrypsin-like, trypsin-like, and caspase-like activities) and two 19S regulatory particles (recognise ubiquitinated proteins, unfold and thread them into the 20S core). Bortezomib (boronic acid dipeptide) reversibly inhibits the chymotrypsin-like site of the 20S proteasome. Carfilzomib (epoxyketone tetrapeptide) irreversibly inhibits the same site with greater selectivity. Cancer cell sensitivity: myeloma cells produce massive amounts of immunoglobulin, generating extraordinary levels of misfolded protein waste that must be proteasomally degraded. Proteasome inhibition overwhelms this already-stressed system → ER stress → unfolded protein response → apoptosis. Normal cells, with lower protein synthesis rates, are more tolerant. Bortezomib-induced peripheral neuropathy is an important dose-limiting toxicity; carfilzomib has less neurotoxicity but greater cardiotoxicity risk.