– SIM1 is a potent and selective trivalent PROTAC®Degrader based on BET bromodomain inhibitors linked to a Von Hippel Lindau (VHL) ligand via branched linkers. SIM1 degrades all BET family proteins with a preference for BRD2 (DC50values = 0.7 nM, 1.1 nM and 3.3 nM for BRD4, BRD2 and BRD3, respectively). SIM1 degrades BRD2 more significantly and rapidly than BRD3 and BRD4, and degrades BET proteins with a higher potency than a bivalent degrader. SIM1 also decreases protein levels for Myc and HMOX1 and induces apoptosis in prostate cancer cells.