A Lipid Prodrug Strategy Enhances Targeted Protein Degrader CNS Pharmacokinetics

Targeted protein degraders that recruit the von Hippel–Lindau E3-ligase complex often have poor physicochemical properties, requiring extensive medicinal chemistry optimization prior to use in hypothesis-testing experiments in vivo and with few blood–brain barrier permeable examples disclosed. In this study, we systematically examine a panel of fatty acid promoieties as agents to enhance degrader pharmacokinetics and BBB-exposure. We characterize effects on cellular E3-ligase engagement, cellular BRD4 degradation kinetics, murine plasma stability, and murine blood plasma and brain pharmacokinetics and pharmacodynamics. We identify degrader prodrugs with significantly improved CNS exposure relative to the parent degrader. This led to successful BRD4 degradation in perfused brain samples, demonstrating that fatty acid promoieties can accelerate progress toward proof of principle in vivo experiments for CNS degrader projects.