In our previous work, we demonstrated that an amide-to-ester substitution at the tert-Leu of the von Hippel-Lindau (VHL)-recruiting ligand can increase membrane permeability. While effective, this ester modification yielded only a modest increase in permeability over their amide counterparts due to the relatively high steric shielding at this position from the β-branched amino acid sidechain. We hypothesized that alternatively, substituting the amide connecting the linker to the POI warhead for an ester would lead to a larger increase in permeability. Therefore, to build on our proof-of-concept study, we developed a systematic set of compounds to test this hypothesis across a wide range of lipophilicities (ALogP) and linker lengths. By applying the insights from these model compounds, we show that the correct combination of an amide-to-ester substitution and ALogP modulation dramatically increased the membrane permeability of known bromodomain and extra terminal (BET) protein targeting PROTACs, MZ1 and ARV-771. These subtle structural modifications have also led to an increased ability to degrade BET proteins and induce cytotoxicity, while maintaining both stable ternary complex formation and plasma stability.