Noticeably, MZ1 (21) formed the strongest Brd4 BD2 :PROTAC:VHL complex (Kd ternary = 1.5 nM, α = 54), values comparable to earlier work by Roy et al. (α = 55), with 28 forming the weakest (Kd ternary = 21 nM, α = 7) out of the series. When comparing MZ1 (21) and ARV-771 (22), 22 showed near equipotent ternary binding to 21 (Kd ternary = 2.5 nM). However, the complex induced by 22 was 4-fold less cooperative (α = 13) than the complex induced by 21 (α = 54). Despite this reduced cooperativity, 22 was a more potent degrader across all three BET domains and was more cytotoxic in both cell lines than 21 (Figure ). However, due to the expected differences in ternary complexes formed by 22 and 21, it is difficult to dissect whether the major factor in the improved cellular activity of 22 over 21 is a 2-fold higher VHL binding affinity (Kd binary = 34 nM and 81 nM, respectively) or the 20-fold increase in membrane permeability of 22 over 21 (Pe = 0.2 x 10-6 cm/s and 0.01 x 10-6 cm/s, respectively, Table and SI Table ). Either way, this does suggest that some combination of increased VHL binding and membrane permeability can compensate for reduced cooperativity, albeit at the expense of an earlier onset of the hook effect.