Molecular Degraders: A Comprehensive Review of Small MoleculeInduced Protein Degradation Strategies

Abstract: Molecular degraders represent a ground-breaking class of small molecules revolutionizing drug discovery through the selective elimination of disease-causing proteins, including those previously deemed "undruggable." This review provides a critical analysis of the design and mechanistic intricacies of molecular degraders, encompassing PROTACs, molecular glues, and SNIPERs, with a focus on their reliance on ubiquitin-mediated protein degradation pathways. Key themes include advancements in E3 ligase selection, the principles guiding ternary complex formation, and the role of structural dynamics in optimizing degrader activity and selectivity. The data for this review was collected from various databases such as Science Direct, United States National Library of Medicine (Pubmed), Google Scholar, Elsevier, Springer, and Bentham. Novel findings, such as the development of non-canonical degrader approaches and their preclinical successes, are examined alongside therapeutic applications in oncology, neurodegenerative diseases, and infectious disorders. Challenges, including resistance mechanisms, safety concerns, and pharmacokinetic limitations, are evaluated to provide a holistic perspective. This review not only highlights the transformative potential of molecular degraders but also identifies future directions and critical gaps that could drive innovation in targeted protein degradation and precision medicine.