PROTACs: A New Era of Targeted Protein Degradation in Drug Discovery and Therapeutics – Recent Advances, clinical translation, Challenges and Future Perspectives

Targeted protein degradation represents a paradigm shift in drug discovery, circumventing the limitations of conventional occupancy-driven inhibitors. Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that simultaneously engage a protein of interest (POI) and recruit an E3 ubiquitin ligase to promote polyubiquitination and proteasomal degradation of the target protein. Since their inception in the early 2000s, PROTAC technology has evolved from peptide-based constructs to small-molecule degraders with improved pharmacokinetic profiles. This review provides a comprehensive analysis of the molecular architecture, mechanism of action, and current state of PROTAC development through 2026. We discuss the utility of different E3 ligases (VHL, cereblon, MDM2, IAP), design principles governing PROTAC efficacy, and emerging optimization strategies incorporating artificial intelligence and machine learning. Major therapeutic applications include oncology (targeting androgen receptor, estrogen receptor, BRD4, BTK), neurodegenerative disorders (tau, α-synuclein), and inflammatory diseases. Currently, multiple PROTAC degraders have advanced to clinical development, with dBET1 (targeting BRD4), PROTAC MT-802 (ARv7), and others undergoing human evaluation. However, significant challenges remain, including high molecular weight, poor cell permeability, metabolic instability, potential for resistance development, and off-target degradation. Recent innovations such as photoactivatable PROTACs, tissue-selective degraders, and dual-targeting approaches show promise in addressing these limitations. The expansion of the E3 ligase toolbox, improved formulation strategies, and integration of computational methods are expected to accelerate clinical translation. This review critically evaluates current evidence, identifies unresolved scientific questions, and provides perspective on the role of targeted protein degradation in the future pharmaceutical landscape.