Navigating PROTACs in Cancer Therapy: Advancements, Challenges, and Future Horizons

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Abstract
Proteolysis Targeting Chimeras (PROTACs) have revolutionized cancer therapy by offering a selective and innovative approach to degrade key oncogenic proteins associated with various malignancies. These hybrid molecules exploit the ubiquitin‐proteasome system, facilitating the degradation of target proteins through an event‐driven mechanism, thereby overcoming drug resistance and enhancing selectivity. With diverse targets including androgen receptors, BTK, estrogen receptors, BET proteins, and BRAF, PROTACs offer a versatile strategy for personalized cancer treatment. Advantages of PROTACs over traditional small molecule inhibitors include their ability to operate at lower concentrations, catalyzing the degradation of multiple proteins of interest with reduced cytotoxicity. Notably, PROTACs address challenges associated with traditionally “undruggable” targets, expanding the therapeutic landscape of cancer therapy. Ongoing preclinical and clinical studies highlight the transformative potential of PROTACs, with promising results in prostate, breast, lung, melanoma, and colorectal cancers. Despite their potential, challenges persist in optimizing physicochemical properties and enhancing bioavailability. Further research is needed to refine PROTAC design and address complexities in molecule development. Nevertheless, the development of oral androgen receptor PROTACs represents a significant milestone, demonstrating the feasibility and efficacy of this innovative therapeutic approach. This review provides a comprehensive overview of PROTACs in cancer therapy, emphasizing their mechanism of action, advantages, and challenges. As PROTAC research progresses, continued exploration in both preclinical and clinical settings will be crucial to unlocking their full therapeutic potential and shaping the future of personalized cancer treatment.

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