Project Summary Targeted protein degradation is an exciting new strategy in drug discovery. Such drugs have several potential advantages: (1) new protein targets must be synthesized to reverse the effect of the drug, potentially prolonging efficacy; (2) all the domains of the target protein are inactivated, potentially eliciting different responses than inhibition of a single active site; (3) each drug molecule can inactivate multiple target molecules, making efficacy event-driven rather than occupancy-driven, potentially lowering dose and (4) simple binders can be converted into functional compounds, which may address targets considered “undruggable”. The rational design of drugs inducing target degradation has almost exclusively focused on a single over-arching strategy: localization of the target protein to a ubiquitin E3 ligase. The primary role of ubiquitination is to localize the target protein to the proteasome, and experiments from several laboratories demonstrate that proteasome localization is sufficient to induce degradation. These observations suggest a ubiquitin-independent strategy for targeted protein degradation, wherein a target recognition ligand is linked to a proteasome binding ligand (proteasome recruiter). Direct localization to the proteasome avoids issues with E3 ligase localization strategies. Proteasome recruiters also have the potential to be tissue, compartment and cancer-specific. The goal of this transformative grant is to demonstrate the feasibility of proteasome recruiters using three strategies: (1) Localization to the 19S regulatory particle; (2) Localization to a proteasome shuttle factor and (3) localization to the alpha ring of the 20S proteasome.