The Exploration for the Bioavailability of PROTAC

Proteolysis-targeting chimeras (PROTACs) represent a paradigm shift in drug discovery, offering the potential to target previously undruggable proteins through event-driven pharmacology. However, their heterobifunctional architecture inherently resides in the beyond-Rule-of-Five (bRo5) chemical space, posing formidable challenges to bioavailability, membrane permeability, and metabolic stability. This chapter systematically examines the physicochemical landscape of PROTACs, dissects the multifaceted drug metabolism and pharmacokinetics (DMPK) barriers they encounter, and provides a comprehensive overview of strategies developed to overcome these obstacles. The discussion further encompasses the influence of administration route on bioavailability and strategies for molecular structure optimization, before addressing bioavailability enhancement approaches, including conditional prodrug activation, chemical derivatization, targeted conjugates, and formulation development, and experimental models for preclinical assessment, culminating in mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) modeling for clinical translation. By integrating medicinal chemistry, pharmacokinetics, and pharmaceutical science, this work provides a foundational reference for researchers advancing PROTACs from discovery to clinical application.