Targeted Protein Degradation via the Ubiquitin-proteasome System: Emerging Advances and Therapeutic Challenges of...

Proteolysis-targeting chimeras (PROTACs) are an emerging therapeutic technology in medicinal chemistry that induces selective degradation of target proteins through the ubiquitin-proteasome system. This review aims to summarize recent advances in PROTAC design, mechanisms of action, therapeutic applications, clinical development, and emerging strategies for overcoming current limitations.

A structured literature search was conducted using PubMed, Scopus, Web of Science, and Google Scholar for studies published between January 2010 and December 2025. Search terms included "PROTACs," "proteolysis-targeting chimeras," "targeted protein degradation," "E3 ligase," "protein degradation," and "PROTAC clinical trials." Studies addressing PROTAC design, mechanisms, medicinal chemistry, therapeutic applications, and clinical development were included. Articles unrelated to targeted protein degradation, duplicate publications, non-relevant studies, and publications lacking sufficient scientific information were excluded.

The literature indicates that PROTACs can achieve efficient and selective degradation of disease-associated proteins, offering advantages over conventional occupancy-based inhibitors. Advances in E3 ligase recruitment, linker optimization, bifunctional degrader design, photoactivatable PROTACs, and dual-target degraders have substantially expanded the potential of this platform. Several PROTAC candidates have progressed into clinical development, supporting their translational potential.

Despite significant progress, challenges remain, including poor solubility, limited oral bioavailability, pharmacokinetic constraints, tissue-specific delivery, and potential off-target effects. Computational modeling, personalized medicine, and improved drug-delivery systems may facilitate more rational and efficient PROTAC development.

PROTACs represent a promising approach for targeted protein degradation and may expand the druggable proteome. Continued advances in medicinal chemistry, pharmacology, computational design, and delivery technologies are essential for translating PROTACs into effective clinical therapies.