Targeted protein degradation: building a platform for biomolecule clearance

Targeted protein degradation (TPD) technology represents a revolutionary approach that hijacks cellular degradation systems to selectively eliminate disease-related proteins, overcoming the limitations of traditional inhibitors that require active sites on target proteins. This review systematically elucidates the molecular mechanisms of TPD, categorizing them into two core mechanisms: degron tagging and proximity-induced degradation, and analyzes the characteristics of bifunctional chimeras versus molecular glues from a molecular design perspective. The article comprehensively reviews the three major biological pathways based on the ubiquitin-proteasome system, endosome-lysosome pathway, and autophagy-lysosome pathway, as well as the clinical translation of molecular glue drugs and innovative advancements of frontier technologies such as LYTAC and ATTEC. With PROTAC molecules like ARV-471 entering phase III clinical trials, TPD technology is evolving from “protein degradation” to “precise clearance of biomolecules”, offering breakthrough therapeutic strategies for cancer, neurodegenerative diseases, and other fields.