proteasometargeting

Proteasome targeting refers to strategies that modulate the proteasome–a central component of the ubiquitin–proteasome system that degrades most intracellular proteins–to influence protein turnover. The term encompasses proteasome inhibitors, proteasome activators, and approaches that direct proteins to degradation via ubiquitination and the proteasome, such as proteolysis-targeting chimeras (PROTACs) and related molecular glues.

The 26S proteasome consists of a 20S core particle providing proteolytic activities and a 19S regulatory particle that recognizes ubiquitinated substrates. The main catalytic activities reside in the β5 (chymotrypsin-like), β2 (trypsin-like), and β1 (caspase-like) subunits. Inhibitors bind these active sites to block protein degradation. Clinically, proteasome inhibitors such as bortezomib, carfilzomib, and ixazomib are approved for multiple myeloma and certain lymphomas; they can cause peripheral neuropathy, cytopenias, and infections.

Proteasome activators and modulators aim to enhance proteasomal degradation, a concept under study for diseases characterized by the buildup of misfolded proteins, though few if any have achieved routine clinical use.

Proteolysis-targeting strategies recruit E3 ubiquitin ligases to a target protein, tagging it with ubiquitin and routing it to the proteasome for destruction. PROTACs and molecular glues exemplify this approach and are being explored across oncology and other areas.

Challenges include achieving selectivity, avoiding unintended degradation of proteins, and managing resistance and toxicity. Proteasome-targeting remains a dynamic field with approved therapies for cancer and ongoing research into broader applications and safety profiles.