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Targeted protein degradation: therapeutic potential and challenges of PROTACs and molecular glues KCI 등재
pp.21-34
Targeted protein degradation (TPD) is an emerging therapeutic strategy that leverages the natural protein degradation systems of cells to eliminate disease-associated proteins selectively. Unlike traditional small molecule inhibitors, which merely suppress protein activity, TPD degrades target proteins directly, offering a novel approach to addressing undruggable proteins. The two most extensively studied TPD technologies, proteolysis-targeting chimeras (PROTACs) and molecular glues (MGs), utilize the ubiquitin–proteasome system to induce TPD. PROTACs function as bifunctional molecules that recruit an E3 ubiquitin ligase (E3 ligase) to a target protein, leading to its ubiquitination and subsequent degradation, while MGs enhance protein–protein interactions to facilitate ubiquitination and protein clearance. These approaches have shown promising therapeutic potential in treating cancer, neurodegenerative disorders, and autoimmune diseases, with several compounds currently undergoing clinical trials. Despite these advances, challenges such as limited bioavailability, pharmacokinetic constraints, and target selectivity remain obstacles to the widespread application of TPDbased therapies. Recent developments, including the discovery of novel E3 ligases, linker optimization, and AI-driven drug design, have addressed these limitations, paving the way for the next generation of precision-targeted therapeutics. This paper provides a comprehensive overview of the mechanisms, applications, and future directions of PROTACs and MGs in drug discovery, highlighting their potential to revolutionize modern targeted therapy.
INTRODUCTION
MECHANISM OF TARGETED PROTEIN DEGRADATION
THERAPEUTIC APPLICATIONS OF TARGETED PROTEINDEGRADATION
CHALLENGES AND FUTURE DIRECTIONS
CONCLUSION
REFERENCES
