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Proteolysis-targeting chimeras in cancer therapy: Targeted protein degradation for next-generation treatment
Yamile Abuchard Anaya1,2, Mariana Barragan1,2, Ricardo Pequeno Bracho1,2,3
1Division of Cancer Immunology and Microbiology, Medicine, and Oncology Integrated Service Unit, School of Medicine, The University of Texas Rio Grande Valley, McAllen, Texas, USA.
Abstract:
Proteolysis-targeting chimeras (PROTACs) have the potential to revolutionize cancer treatment by specifically targeting and degrading oncogenic proteins. Using the ubiquitin-proteasome system, PROTACs allow the selective degradation of disease-causing proteins, including those traditionally deemed "undruggable" by conventional small-molecule inhibitors. By catalytically eliminating rather than inhibiting proteins, PROTACs provide sustained target suppression with lower doses and reduced toxicity. Their bifunctional design linking a protein of interest to an E3 ligase drives targeted ubiquitination and subsequent proteasomal degradation. Recent progress demonstrates promise in treating solid and hematologic malignancies, with several candidates advancing to clinical trials. This review provides a comprehensive overview of developing PROTACs, from understanding their mechanism to clinical applications, and highlights their emerging role in overcoming drug resistance and advancing the limits of cancer treatment. In addition, the authors discuss the challenges of optimizing PROTACs, including issues related to pharmacokinetics, E3 ligase compatibility, and the delivery of PROTACs to tumors. With their modularity, adaptability, and precision, PROTACs represent a next-generation platform for personalized cancer therapy across various patient groups.
Insights
Proteolysis-targeting chimeras (PROTACs) offer a novel approach to cancer therapy by degrading disease-causing proteins. This method promises more effective and less toxic treatments for various cancers.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Proteolysis-targeting chimeras (PROTACs) leverage the ubiquitin-proteasome system for targeted protein degradation.
- PROTACs offer a new strategy for targeting proteins previously considered undruggable by conventional inhibitors.
Purpose of the Study:
- To provide a comprehensive review of PROTAC development, mechanism, and clinical applications in cancer treatment.
- To highlight the potential of PROTACs in overcoming drug resistance and advancing personalized cancer therapy.
Main Methods:
- Review of existing literature on PROTAC technology, mechanism of action, and preclinical/clinical studies.
- Analysis of PROTAC design principles, including bifunctional molecule structure and E3 ligase recruitment.
Main Results:
- PROTACs demonstrate promise in treating both solid and hematologic malignancies, with several candidates in clinical trials.
- Catalytic degradation by PROTACs leads to sustained target suppression with potentially lower doses and reduced toxicity compared to inhibitors.
Conclusions:
- PROTACs represent a promising next-generation platform for personalized cancer therapy due to their modularity and precision.
- Challenges in PROTAC optimization include pharmacokinetics, E3 ligase selection, and tumor delivery, which require further research.
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