It has been suggested that short alkyl linkers may be better for PROTAC permeability, as they help minimize the already high topological polar surface area (TPSA) and the number of HBAs present. However, this hypothesis has not been fully tested. We have previously shown that the effect of the linker on PROTAC permeability can be confounded by hydrogen bonding and overall lipophilicity. For this study, we designed a systematic set of four compounds to assess the effects of linker length and composition on permeability by reducing the POI-ligand mimic to a simple benzyl group attached by an amide. The linkers varied from a short alkyl linker (3) to PEG-based linkers ranging from 1-to 3-PEG units in length (15 -17, respectively) (Figure , Table ). The alkyl-linked compound 3 had the highest permeability. Permeability decreased with increasing PEG chain linker length with 17 (3-PEG unit linker) showing no detectable permeability (Figure , SI Table ). This decrease in permeability is likely caused by a decrease in ALogP due to the increasing PEG chain length, consistent with the linear relationship between ALogP and permeability in this lipophilicity range (Table ). 10 -6 cm/s), moderate (1 x 10 -6 cm/s < Pe < 5 x 10 -6 cm/s), and good (Pe > 5 x 10 -6 cm/s) membrane permeability.