Proteolysis Targeting Chimera (PROTACs) in Cancer: From Molecular Mechanisms to Therapeutic Opportunities

Cancer ranks as the second leading cause of mortality around the globe, only behind cardiovascular ailments, largely owing to challenges in early detection and a significant recurrence rate following standard treatments. Chemotherapy is effective in suppressing the swift proliferation of malignant cells; however, it also adversely impacts normal cells that replicate quickly. Consequently, it is essential to create alternative and safer treatment approaches that are more efficient. The intracellular ubiquitin-proteasome system for targeted protein destruction is an emerging technology in the development of therapeutic agents for personalized medicine. Proteolysis targeting chimeras (PROTACs), composed of two compounds that bind to a target protein and an E3 ubiquitin ligase, have offered promising strategies in the treatment of multiple cancers. PROTACs have shown potential in overcoming resistance mutations by degrading cancer-associated proteins, including resistant variants, while requiring only low concentrations within cells. The present article reviews the biochemical structure of PROTAC and highlights PROTAC technology in the treatment of cancer. The application of PROTACs in targeting main cancer-related proteins, including Kirsten rat sarcoma virus (KRAS), epidermal growth factor receptor (EGFR), and anaplastic lymphoma kinase (ALK) mutations, has demonstrated promising approaches in the effective treatment of cancer in preclinical models. Additionally, the review provides hints at the current advances in the PROTAC technology for cancer therapy.