PROTACs: Principles and Mechanisms

Proteolysis Targeting Chimeras (PROTACs), a groundbreaking technology that has revolutionized the landscape of targeted protein degradation and therapeutics, is a clinically validated strategy, as seen from significant number of clinical candidates at various stages of development. The present chapter focuses on the principles underlying PROTAC design, including their tripartite structure comprising a protein-of-interest (POI) ligand, an E3 ubiquitin ligase ligand, and a linker with defined chemistry, laying the groundwork for understanding the elegance of PROTACs in orchestrating targeted protein degradation, emphasizing the strategic design considerations that govern their efficacy and specificity. Next, a comprehensive exploration of the mechanisms of action of PROTACs, detailing the sequential steps from target protein recognition to ubiquitination and subsequent proteasomal degradation, is presented. The critical parameters that influence their pharmacological profiles, including the choice of E3 ligase, the nature of the linker, and the dynamics of the ternary complex formation, are highlighted with the help of apt examples from recent advancements that illustrate the iterative process of PROTAC development, from conceptualization to clinical application. A forward-looking perspective on the challenges and future directions in the field of targeted protein degradation is presented. Overall, an in-depth analysis of PROTAC technology, from its conceptual underpinnings to its application in drug discovery, with particular emphasis on the principles and mechanisms of PROTACs are presented, thereby conveying the transformative potential of PROTACs, setting the stage for their continued evolution and integration into the next generation of biomedical research and therapeutic development.