PROTAC Technology: A Critical Appraisal of Targeted Protein Degradation-From Mechanistic Principles to First-in-Class Clinical Approval

Proteolysis-Targeting Chimeras (PROTACs) have revolutionized small-molecule pharmacology by harnessing the ubiquitin-proteasome system to achieve catalytic, event-driven degradation of disease-associated proteins rather than transient inhibition. This approach has emerged as a promising therapeutic strategy for targeting conventionally druggable and previously undruggable proteins across multiple disease areas. This review critically appraises the evolution of PROTAC technology from its mechanistic foundations to its first clinical approval. It aims to integrate current knowledge on structural design, ternary complex formation, E3 ligase selection, computational advances, therapeutic applications, clinical progress, and the key challenges influencing future degrader development. A comprehensive critical review of the published literature was conducted by analyzing recent advances in PROTAC design, ubiquitin-proteasome biology, E3 ligase pharmacology, computational and artificial intelligence-assisted discovery methods, preclinical studies, clinical trials, and emerging targeted protein degradation technologies. Evidence from more than thirty clinical-stage PROTACs and recent regulatory milestones was synthesized to evaluate the current status and future prospects of the field. PROTACs comprise three essential components: a protein-of-interest ligand, an E3 ubiquitin ligase recruiter, and a chemical linker that collectively determine ternary complex formation and degradation efficiency. Cereblon and von Hippel-Lindau remain the predominant E3 ligases in clinical development, while emerging ligases such as MDM2, cIAP, RNF114, DCAF15, DCAF16, KEAP1, and FEM1B are expanding the therapeutic landscape. Clinical translation has advanced substantially, highlighted by the Approval of Vepdegestrant (ARV-471), the first marketed PROTAC, whereas agents such as bavdegalutamide (ARV-110) demonstrated biomarker-dependent clinical efficacy. Despite these advances, challenges including limited oral bioavailability, the hook effect, E3 ligase-mediated resistance, and off-target toxicities remain significant. Emerging innovations, including artificial intelligence-guided PROTAC design, tissue-selective E3 ligases, and next-generation degradation platforms such as photo-PROTACs, LYTACs, AUTACs, antibody-PROTAC conjugates, and nano-PROTACs, offer promising strategies to overcome these limitations. PROTAC technology has progressed from proof-of-concept chemical biology to a clinically validated therapeutic modality. Continued advances in medicinal chemistry, computational modeling, biomarker-guided patient selection, and targeted degradation technologies are expected to further expand its clinical applications. Addressing pharmacokinetic limitations, resistance mechanisms, and target selectivity will be critical for realizing the full therapeutic potential of PROTACs in precision medicine.