It is important to consider lipophilicity during compound design to attain molecules with favorable absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. While suggested optimal lipophilicity ranges exist for typical small molecule drugs and bRo5 compounds, design parameters for ideal PROTAC lipophilicity remain unclear. We set out to perform a systematic investigation into the effect of lipophilicity on permeability for a set of seven VHL-based "PROTAC-like" model compounds (1 -7, Figure ). All compounds contained the VHL ligand VH032 as their E3 ligase-targeting ligand. We modulated the compounds' lipophilicities using a variety of simple warheads as surrogates of POI ligands across a range of calculated lipophilicities (ALogP) from 1.2 -6.0. As permeability can be strongly affected by molecular weight (MW) and the number of hydrogen bond donors (HBDs) and acceptors (HBAs), we kept these values in a relatively narrow range (MW = 600 -800, HBD = 3 -4, HBA = 6 -8, SI Table ). Furthermore, we used a short alkyl linker for compounds 1 -7 to eliminate permeability-affecting intramolecular hydrogen bonds (IMHBs) that can be formed between polyethylene glycol (PEG)-based linkers and amide -NHs in other parts of the molecule. We next investigated the effects of lipophilicity on membrane permeability using the parallel artificial membrane permeability assay (PAMPA), a high-throughput permeability assay that is generally well correlated to cell-based permeability measurements. Our group has shown that PAMPA is beneficial for studying compounds with low expected permeabilities due to the assay's low limit of detection. Similar to other types of previously studied compounds, the permeabilities of the model compounds increased with ALogP up to an ALogP of around 4 (cf. 1 -5, Figure -B, SI Table ). Above an ALogP of 4, permeability decreased as ALogP increased (cf. 6 -7) with no detectable permeability for 7, which had an ALogP of 6.0 (Figure , Table ). At these higher ALogP values (>4 -5), compounds begin to lose aqueous solubility and become membrane retained, both of which can reduce passive membrane permeability. The data with this compound series suggests that PROTACs based on VH032 should be designed with an ALogP between 3 -5 to bias them towards higher permeability, similar to other bRo5 compounds. Moreover, the relationship between lipophilicity and permeability offers a route to improve the permeability of PROTACs by making small structural modifications as needed to maintain ALogP within the optimal range. Recently, it has been shown that PROTACs can have a high efflux ratio in cell-based permeability assays. Therefore, we were interested in monitoring both the cell permeabilities and efflux ratios over this broad ALogP range. In bidirectional MDCK-MDR1 cells expressing human Pgp, amides 1 -6 demonstrated generally low cell permeability, though these results were not strongly correlated to PAMPA or lipophilicity. As in PAMPA, 7 was below the limit of detection (Figure , SI Table ). Additionally, amides 1 -6 also had high efflux ratios, suggesting that they undergo active efflux. Interestingly, these efflux ratios were highly correlated to both lipophilicity and PAMPA permeability. Efflux ratios increased with lipophilicity up to an ALogP of around 4, peaking with 5. As with PAMPA permeability, the efflux ratio decreased with increasing lipophilicity at ALogP values above 4 (SI Tables ).