Dual-Action-Only PROTACs.

Proteolysis targeting chimera (PROTAC)-based degraders are highly potent pseudocatalytic drugs, but on-target off-site homing could yield undesirable consequences. We report here a generalizable AND-logic gated PROTAC, where the concurrent presence of two different disease-relevant endogenous stimuli liberates an active protein degrader. We design Dual-Action-Only PROTAC (DAO-PROTAC) molecules that are dormant and can only be activated in the presence of both hypoxia and cathepsin-L to degrade the protein of interest (POI). We also show that the dormancy of DAO-PROTACs translates to considerable mitigation of cytotoxicity, demonstrating the potential advantages over the corresponding free PROTAC and single-stimulus triggerable pro-PROTACs.