We next envisaged that a trifunctional PROTAC could be assembled around a 'core scaffold' connected to each of its three ligands via variable linkers (Fig. ). We reasoned that 1,1,1-tris(hydroxymethyl)ethane, also known as trimethylolethane (TME), could provide fit-forpurpose scaffold because it features three primary alcohol groups in a neopentyl core structure, thus acting as branched, close bioisosteric replacements of PEG units. The achirality of the central quaternary carbon of the TME core could be readily achieved by keeping the chemical linkers to each BET ligand moiety identical. To allow flexibility in exploring the relative constraints between the different monomeric ligands, while at the same time keeping the overall chemical structure as close as possible to those of MZ1 and MT1, we designed three branched PROTACs (SIM1 (3), SIM2 (4) and SIM3 (5)) bearing PEG3 or PEG4 at each linker to the BET ligand (n=3,4), and PEG0 or PEG1 towards the VHL ligand VH032-amine (m=0,1) (Fig. ).