Beyond Inhibition: Emerging Approaches in Ubiquitin–Proteasome‐Mediated Protein Degradation for Precision Targeting

Targeted protein degradation (TPD) represents an emerging paradigm in drug discovery, capable of overcoming the limitations of traditional therapeutic strategies based on protein inhibition. Exploiting the ubiquitin–proteasome system (UPS), TPD allows the selective elimination of pathologically relevant proteins. The most established approaches in TPD are proteolysis‐targeting chimeras (PROTACs) and molecular glue (MG) chemical degraders, which feature distinct molecular architectures and mechanisms of action. Although these approaches have proven highly effective in promoting the selective degradation of target proteins, their use is often accompanied by critical issues related to tissue selectivity and biodistribution. To overcome these limitations, advanced strategies have been developed in recent years that exploit endogenous and exogenous triggers, such as antibody–PROTAC conjugates and PROTAC prodrugs that can be activated by enzymes, redox conditions, hypoxia, light, or radiotherapy, allowing for more precise spatial and temporal control of degradation. Alternative approaches, such as hydrophobic tagging, further expand the available repertoire, circumventing the E3 ligase dependency inherent to PROTAC systems for protein destabilization and confirming the versatility of the TPD platform. In this review, an overview of the most effective and promising approaches in TPD is reported, focusing on the most recent technological advances and reporting key case studies.