From PROTACs to Clinical Reality: A Narrative Review of Targeted Protein Degradation Therapies

This narrative review examines the development, mechanisms, therapeutic applications, and clinical translation of targeted protein degradation (TPD), with particular emphasis on proteolysis-targeting chimeras (PROTACs). TPD represents a therapeutic strategy that induces selective elimination of target proteins by redirecting the cell’s endogenous protein-degradation machinery, offering a mechanistically distinct approach from conventional small-molecule inhibition. The review aims to trace the evolution of PROTAC technology from its early experimental development to contemporary clinical applications and to evaluate the progress, opportunities, and challenges associated with translating targeted protein degradation into effective therapies. The review will synthesize available literature on the molecular principles underlying PROTAC-mediated degradation, including target recognition, E3 ubiquitin ligase recruitment, ternary-complex formation, ubiquitination, and subsequent proteasomal degradation. It will examine key factors influencing degradation efficiency and selectivity, including linker design, ligand affinity, target protein characteristics, E3 ligase selection, cellular context, pharmacokinetic properties, and the concept of event-driven pharmacology. The review will also consider emerging TPD modalities beyond conventional PROTACs, including molecular glues and other approaches designed to achieve targeted elimination of disease-associated proteins. Particular attention will be given to the translational development of TPD therapies, including preclinical evidence, clinical-stage candidates, therapeutic targets, disease indications, and lessons emerging from early clinical studies. The review will assess both the potential advantages of targeted protein degradation and the barriers to clinical implementation, including drug-like properties, oral bioavailability, tissue penetration, toxicity, resistance mechanisms, E3 ligase limitations, target selection, and the identification of appropriate biomarkers and patient populations. The expected outcome is a comprehensive synthesis of the current state of targeted protein degradation, illustrating how PROTACs and related technologies have progressed from a conceptual platform to clinically relevant therapeutic strategies. By integrating mechanistic, preclinical, and clinical evidence, this review will identify major advances in the field, highlight remaining translational challenges, and discuss future directions for the development and clinical application of targeted protein degradation therapies.