Overall, the amides were more stable in plasma than their ester counterparts. This effect was more pronounced for compound pairs with smaller, sterically unhindered POI-ligand mimics, with ≤10% compound loss of the amide compounds at 90 min (1 -4) compared to 60 -90% compound loss at 90 min for their ester counterparts (8 -11) (Table , SI Figure ). Esters 12 -14 contained larger warheads with likely more steric shielding around the susceptible ester. These compounds had much lower compound loss after 90 min (4 -10%, Table , SI Figure ). This reduced hydrolysis, evident with bulky substituents, suggests that amide-to-ester substitutions could be used to increase PROTAC permeability without affecting PROTAC in vivo or in cellulo activity as these larger substituents more closely represent typical POI ligands present in PROTACs.