With this model-toolkit for improving PROTAC permeability in hand, we were curious to determine if we could apply these insights to improve PROTAC permeability and, as a result, their degradation activity. To test this idea, we decided to study two previously published and structurally similar BET-targeting PROTACs, MZ1 (21) and ARV-771 (22). MZ1 is comprised of a pan-selective triazolothienodiazepine BET inhibitor, (+)-JQ1, connected to the VHL-ligand VH032 via a 3-PEG-based linker. ARV-771 uses the same BET-targeting ligand, but differs from MZ1 by having a slightly shorter, more lipophilic linker (minus CH2-O), and containing an extra chiral methyl group at the benzyl position of the VHL ligand. Because both esters and amides at the linkage point of JQ1 are equally effective at binding to BET bromodomains, we reasoned MZ1 and ARV-771 would provide an ideal model system to study the effect of the amide-to-ester substitution without interfering with binary POI binding affinity. Using a combination of amideto-ester substitutions between JQ1 and the linker, and subtle modifications to linker length and composition, we designed and synthesized compounds 23 -28 (Table ) with a goal to improve the degrader activity through increased permeability. (22). For detailed synthetic procedures, see the Supporting Information. *PAMPA Pe values are ×10 -6 cm/s.