Targeted Protein Degradation (PROTACs & Molecular Glues): Mechanisms and Therapeutic Potential

Targeted protein degradation (TPD) has emerged as a transformative therapeutic strategy that overcomes the limitations of traditional occupancy-driven pharmacology. Unlike conventional small-molecule inhibitors that temporarily block protein function, TPD eliminates disease-causing proteins by harnessing the endogenous ubiquitin–proteasome system (UPS). Among TPD approaches, Proteolysis Targeting Chimeras (PROTACs) and molecular glues represent the most advanced and promising modalities. PROTACs and molecular glues have demonstrated significant therapeutic potential in oncology, neurodegenerative disorders, inflammatory diseases, and infectious conditions, with several candidates currently undergoing clinical evaluation. Despite promising progress, challenges such as pharmacokinetic limitations, off-target effects, and optimization of drug-like properties remain. This review provides a comprehensive overview of the molecular mechanisms underlying PROTACs and molecular glues, their design principles, therapeutic applications, and recent advances. Additionally, current challenges and future perspectives are discussed, highlighting the potential of targeted protein degradation as a next-generation paradigm in drug discovery and precision medicine