Proteolysis‐targeting chimeras in cancer therapy: Targeted protein degradation for next‐generation treatment
Yanett Anaya, Mariana Barragan, Ricardo Pequeno Bracho, Salique H. Shaham, Debasish Bandyopadhyay, Elias George, Diane Nguyen, Manish K. Tripathi
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.