From Ubiquitination to Proteasome-Directed Recruiting: Emerging Mechanisms and Therapeutic Potential in Targeted Protein Degradation

Targeted protein degradation has transformed drug discovery by enabling selective elimination of disease-associated proteins. Beyond classical E3 ligase-recruiting degraders, emerging proteasome-directed strategies seek to recruit targets directly to the proteasome, potentially bypassing E3 ligase dependency and ubiquitination requirements. This approach may expand the degradable proteome, but requires proteasome ligands that engage accessible surfaces, tolerate linker attachment, and preserve basal proteasome function. In this Perspective, we summarize recent advances in direct proteasome-targeting degradation, focusing on ligands of the 19S regulatory particle and 20S core particle. We assess how proteasome subunits and binding pockets have been exploited for degrader design and distinguish ligand-level challenges, such as undefined binding sites, immature SAR, and uncertain linker vectors, from degrader-level issues, including cellular exposure, degradation selectivity, off-target effects, and proteostasis liability. These considerations provide a framework for designing next-generation proteasome-recruiting degraders.