Interestingly, in MV4;11 cells, all of the PROTACs became less effective at higher concentrations (10 µM) (Figure ). This was ascribed to be due to the "hook-effect", 70 a wellknown phenomenon with bifunctional PROTAC degraders, where at high concentrations, unproductive binary complexes of PROTAC:E3 ligase and of PROTAC:POI outcompete ternary complex formation (POI:PROTAC:E3 ligase). Moreover, in 22Rv1 cells, all PROTACs, with the exceptions of 21, 24 and 25, exhibited a hook effect to varying degrees (Figure ). Interestingly, 22, 23, 26, 27 and 28 all have PAMPA permeabilities ≥ 0.2 × 10 -6 cm/s and generally higher ALogP values than 21, 24 and 25. This suggests that 22, 23, 26, 27 and 28 likely enter the cell more efficiently, leading to higher intracellular PROTAC concentrations, and thus more pronounced hook effects. On broader terms, this correlation between PAMPA permeabilities and the hook effect further supports that the PAMPA permeabilities measured with our PROTAC set translate into relevant trends in their cellular activity profiles.