These observations suggest that protein degradation with these compounds must be driven by cell permeability rather than ternary complex formation. Indeed, for each matched pair, the ester is more permeable than the parent amide: 25 is more lipophilic and 10-fold more permeable than 21; 26 is more lipophilic and 1.5-fold more permeable than 22; and 28 has the highest PAMPA permeability (Pe = 0.6 × 10 -6 cm/s) of the entire PROTAC series and is 7.5-fold more permeable than 24 (Table , Figure , SI Table ). These results also highlight the utility of PAMPA to ascertain biologically meaningful permeability differences among PROTACs, even among compounds whose absolute permeabilities are very low (<10 -6 cm/s). Taking these data altogether, it is evident that the greater activity of ester PROTACs relative to their amide counterparts is being influenced by their ability to permeate into cells more efficiently, thus, initiating the ternary complex-driven catalytic knock-down of target BET proteins at overall lower dose, resulting in more potent degrader compounds.