We and others have shown that improved PROTAC-induced degradation of BET protein translates to enhanced effect in the viability of BET-dependent cancer cell lines. We therefore moved to evaluate the cytotoxicity of our PROTAC series by assessing the viability of BETsensitive lines MV4;11 (acute myeloid leukemia) (Figure ) and 22Rv1 (human prostate carcinoma) (Figure ). All PROTACs exhibited a marked antiproliferative effect on each cell line, consistent with their activity as degraders. Compounds 22 and 26 gave the most pronounced effect with EC50 values of 18 nM and 4 nM in MV4;11, respectively, and 44 nM and 58 nM in 22Rv1, respectively. Notably, out of the non-methylated VH032-based PROTACs, 28 was the most effective with EC50 values of 53 nM and 250 nM for MV4;11 and 22Rv1, respectively. This compound had the highest PAMPA permeability (Pe = 0.6 × 10 -6 cm/s, Table , SI Table ) suggesting that it permeates membranes more effectively and is thus able to start the catalytic cycle of ternary complex formation, ubiquitination, and degradation at lower compound dose, leading to increased cell antiproliferation. Furthermore, it is because of this catalytic activity at substoichiometric concentration that even a modest improvement in permeability can significantly increase a PROTAC's degradation activity and cytotoxicity.