Composed of two binders and a linker, bifunctional PROTAC degraders typically fall in bRo5 space. Chemists have recently been pushed to shift away from designing molecules in the traditional Ro5 chemical space as more bRo5 compounds are shown to be cell active, and developable in vivo, including being orally bioavailable. However, having general guidelines for physicochemical design parameters for bRo5 compounds like PROTACs is critical to improve their chances to be useful cellular probes and to be developable as drugs. In response to this pressing need, some have attempted to improve permeability, solubility, and efflux ratios through linker modifications. In contrast, others have also attempted to reduce the number of amide bonds (HBDs) to improve the physicochemical properties of PROTACs. We and others have attempted to develop systematic studies of PROTAC physicochemical properties and new methods to study these properties. In this study, we have shown that PAMPA is a reliable predictor of PROTAC permeability that translates relatively well into their cellular activity profiles. This has allowed us to develop strategies of improving PROTAC potency by improving permeability despite the previously suggested propensity of PROTACs to actively undergo efflux. We used a systematic investigation of linker lengths and lipophilicity combined with amide-to-ester substitutions to improve the permeability of "PROTAC-like" model compounds. We demonstrated that the PROTACs studied herein achieve the highest permeability at moderate lipophilicities (3 -5) and that, within this range, increasing the lipophilicity of a compound leads to increased permeability, as has been seen other beyond Ro5 compounds. Designing compounds in this range (which we have found to contain more permeable compounds) is also likely to reduce toxicity. We also demonstrate that amide-to-ester substitutions can increase PROTAC permeability in this ALogP range as well. Therefore, ester-containing compounds in this lipophilicity range are likely to have better overall pharmacokinetic properties than amide compounds or those with higher lipophilicities. Finally, though esters are more prone to hydrolysis and therefore tend to be less stable in plasma, we discovered that adding steric bulk to the chemical space surrounding the area (i.e., near the warhead) drastically reduces compound degradation in the plasma. Therefore, amide-to-ester substitutions remain a viable option for PROTAC pharmacokinetic improvement, leading to more compound reaching its intracellular target. In each amide-to-ester PROTAC matched pair, we have demonstrated that this simple functional group conversion can lead to significant increases in PROTAC bioactivity, despite esters showing weaker binding affinity than their amide counterparts. We therefore provide what are, to our knowledge, unprecedented examples of optimizing PROTAC degradation activity through systematic rational improvements in compound cell permeability. It is clear that the increase in lipophilicity and permeability shown by the esters and linker modified compounds relative to amides has a positive effect on cellular activity and should be considered when designing future degraders, while attempting to retain favorable productive ternary complex formation. Amide-to-esters substitution thus provide a simple and convenient bioisosteric replacement that we anticipate will find wide utility as an attractive strategy for development and optimization of PROTACs, as well as other emerging beyond Ro5 compounds of chemically-induced proximity.