Targeted Protein Degradation: Mechanisms, Therapeutic Applications, Challenges, and Future Directions

Targeted Protein Degradation (TPD) has emerged as a transformational therapeutic technique for removing disease-causing proteins by utilising the cell's natural degradation systems, such as the ubiquitin-proteasome and lysosomal pathways. Unlike conventional inhibitors, TPD can target previously "undruggable" proteins, such as transcription factors and scaffolding proteins. Key modalities include proteolysis-targeting chimaeras (PROTACs), molecular glues, and lysosome-directed techniques like LYTACs and AUTACs. TPD has shown tremendous potential in oncology, neurological disorders, and immune-mediated diseases, with clinical candidates such as ARV-471 displaying good efficacy. TPD has several advantages, including catalytic activity, increased selectivity, and the ability to overcome drug resistance. However, issues persist in terms of oral bioavailability, off-target effects, and E3 ligase diversity. Emerging technologies like as artificial intelligence-driven design, novel delivery systems, and extended E3 ligase discoveries are propelling innovation in the field. As clinical results mount, TPD is set to transform drug research and treatment approaches for a wide spectrum of disorders.