Targeted protein degraders: Blood–brain barrier permeability and central nervous system exposure

Innovative approaches are essential for treating central nervous system (CNS) diseases that present severe neurological manifestations and low survival rates. Delivering chemical or biological molecules across the blood–brain barrier (BBB) at therapeutically effective concentrations to treat CNS pathologies is a significant challenge. The urgent need for novel treatments targeting disease-causing proteins has propelled targeted protein degraders (TPDs) into the spotlight. TPDs have emerged as promising therapeutics for the treatment of CNS proteinopathies, characterized by the accumulation of misfolded protein aggregates. Given their structural features, the BBB permeability and CNS bioavailability of TPDs may seem improbable. However, several TPDs have demonstrated measurable concentrations in cerebrospinal fluid and the brain. Understanding the mechanisms behind their permeability across the BBB could open new avenues for the development of more effective TPD-based therapies for CNS proteinopathies. This review explores the absorption, distribution, metabolism, and excretion properties of TPDs in relation to brain pharmacokinetic parameters. It also delves into the likely interactions of advanced-stage TPDs with drug transporters and possibilities of disruption-propelled versus B-B barrier permeability-driven CNS bioavailability. Finally, it provides critical insights into the BBB permeability aspects of TPDs, uncovering new dimensions for future research.