Proteasome

Notes

original target text: Proteasome inhibitor

The proteasome is a large, barrel-shaped protein complex found in essentially all cells, responsible for degrading proteins that are damaged, misfolded, or no longer needed. Proteins destined for destruction are tagged with a small protein called ubiquitin, which marks them for delivery into the proteasome's catalytic core. This ubiquitin-proteasome system helps regulate the cell cycle, DNA repair, and stress responses, and it clears unfolded protein burden that would otherwise accumulate.

Proteasome inhibitors block the enzymatic activity of this complex, preventing degradation of its normal protein substrates. Cells that produce large quantities of protein, most notably antibody-secreting plasma cells, are especially dependent on efficient proteasome function to avoid toxic buildup of misfolded proteins. When the proteasome is inhibited, these cells accumulate stress signals and can undergo programmed cell death. This vulnerability is the biological rationale for using proteasome inhibitors in blood cancers characterized by abnormal plasma cell proliferation, where malignant cells are disproportionately sensitive to disruption of protein turnover compared with most healthy tissue.

Because the proteasome is essential in nearly every cell, inhibiting it broadly rather than selectively affects a fundamental housekeeping process, which shapes both the therapeutic use and the tolerability profile of drugs acting on this target.