20S proteasome

Class

Novel oral proteasome inhibitor (SHY Therapeutics)

Pathway

Ubiquitin-proteasome protein degradation pathway

The 20S proteasome is a large barrel-shaped protein complex that serves as the primary machinery cells use to degrade damaged, misfolded, or short-lived regulatory proteins. It works together with the ubiquitin system, which tags proteins destined for destruction, in what is collectively called the ubiquitin-proteasome pathway. This pathway maintains protein quality control and regulates the levels of proteins that control cell division, survival, and stress responses. Certain cancer cells, particularly those that produce large amounts of protein such as plasma cell malignancies, are especially dependent on efficient protein turnover to avoid accumulating toxic misfolded proteins. Inhibiting the proteasome causes these unwanted proteins to build up, triggering a cellular stress response that can lead to programmed cell death preferentially in cells with high protein-production demands. Proteasome inhibition has therefore become an established therapeutic strategy in oncology, most notably in blood cancers. Oral small-molecule proteasome inhibitors aim to provide this same mechanism through a formulation that avoids the need for injection, potentially improving convenience of chronic dosing schedules while retaining the underlying biological rationale of disrupting protein degradation in malignant cells.