In all cases, PROTACs formed preferential and more positively cooperative ternary complexes with the second bromodomain (BD2) of each BET protein over the first bromodomain (BD1), consistent with what is observed with MZ1 (see refs. and data herein, cf. 21). All PROTACs displayed cooperative ternary complexes with all BET BDs (α > 1, Figure , SI Table ). Interestingly, all esters, albeit retaining positive cooperativity with each BET BD, were slightly less cooperative than their amide counterparts. Ternary complexes between Brd4 BD2 , PROTAC, and VHL formed the strongest and most cooperative ternary complex, as in the case of MZ1 (21). This can be seen by a left-shift in the FP displacement curve when the bromodomain is present (Figure ). Interestingly, 21, 25, 23 and 27, which all have the same linker length, follow the same intra-BET bromodomain cooperativity profile (Figure ), suggesting that these compounds form similar ternary complexes to one another. In contrast, compounds 22, 26, 24 and 28, which all contain the same, shorter linker, were found to be less discriminatory between individual bromodomains. Based on these results we conclude that these four compounds likely form ternary complexes that, while similar to one another, are significantly different from the structurallyresolved complex of MZ1 (21). Importantly, within these sets of compounds with the same linker length, each amide-to-ester matched pair showed identical intra-BET selectivity profile, strongly suggesting that each pair forms highly similar ternary complex.