UC San Diego

Proteolysis targeting chimeras (PROTACs) are a promising class of molecular probes that can elicit degradation of classically undruggable targets. This capability comes with a large size (>1000Da), and thus reduced cell permeability: this extends to the blood brain barrier (BBB), effectively limiting the employment of PROTACs as in vivo probes for pharmacologically relevant targets that lie in the central nervous system. Strategies for small molecule inhibitors generally cannot be applied to PROTACs due to their large size, however one such approach that shows promise is the prodrug approach, in which a labile attachment known as a promoiety is attached to a pharmacologically active site of a drug with the purpose of improving physicochemical properties. To date, no studies exist which utilize the prodrug approach as a means of improving the BBB permeability of PROTACs. The work herein describes our efforts to develop a generalizable strategy to improve the BBB permeability of PROTACs through the prodrug approach, as to expand the degradable proteome into the CNS.