Notably, the esters achieved their peak permeability at a lower lipophilicity than the amides, at ALogP = 3.2 -3.8 vs. ALogP = 4, respectively (Figure ). This ability to achieve higher membrane permeability at lower lipophilicities has important implications for drug development, as increased lipophilicity has been linked to increased toxicity and decreased specificity in addition to other liabilities associated with diminished solubility. Though not as apparent as the PAMPA results, ester compounds had MDCK permeabilities that were also greater than or equal to their amide counterparts for the most part (Figure ). These MDCK cell and PAMPA permeabilities followed similar trends within the ester compound series, with 9 and 10 having the peak permeabilities in both assays (Pe = 6.5 x 10 -6 cm/s, Figure , SI Table ). These two ester compounds (9 and 10) also had very high efflux ratios in the MDCK assay compared to their amide counterparts (2 and 3, respectively). High efflux likely contributes to the diminished improvement in the MDCK cell permeabilities of the esters relative to the amides, compared to those improvements observed in PAMPA. Much like the amide compounds, the ester series had a high efflux ratio that was similarly correlated to lipophilicity (SI Table ). Overall, amide-to-ester substitution offers a highly effective strategy to improve PROTAC permeability over a wide range of lipophilicities.