Furthermore, BRD4 degradation mediated by 86 was remarkably slow compared to the rapid degradation mediated by 27 (Supplementary Figure ), likely due to reduced cellular permeability. of the compound. Surprisingly, 86 also had a marked antiproliferative effect on VHL/CRBN dKO cells (EC50 = 15 nM), which was found to be near equipotent to WT cells. This suggests that 86 is acting more as a potent bivalent BET inhibitor as there is no enhanced cytotoxic effect through BET degradation.