As an amide-to-ester substitution was found to improve the permeability of our first compound series of model compounds (1 -14), we decided to make a second set of amide-to-ester compound matched pairs and synthesized esters 10, 18 -20 (Figure ). The esters all had detectable permeabilities that were 8-to 19-fold more permeable than their amide counterparts (Figure , SI Table ). Unlike the amides, which all had poor permeabilities (Pe < 1 x 10 -6 cm/s), all the esters had modest to good permeabilities (1 x 10 -6 cm/s < Pe < 5 x 10 -6 cm/s). Thus, an amide-to-ester substitution improves permeability and offers more flexibility in compound design as a wider range of ester linkers are more likely to be permeable than their amide counterparts. This design flexibility is crucial since small modifications to the linker can significantly affect PROTAC bioactivity, ternary complex formation, and subsequent targeted degradation.