When envisaging the heterotrivalent PROTACs, we kept several design criteria in mind. The linkage between the VHL ligand VH032 and the BET ligand JQ1 should allow for VHL-driven BET degradation; and similarly, the linkage between CRBN-binding thalidomide and JQ1 should allow for CRBN-driven BET degradation. In contrast, we intended for the linkage between VH032, and thalidomide minimize any crossdegradation between VHL and CRBN. To link VH032 with JQ1, we used the linker lengths of active VHL recruiting trivalent, SIM1, 11 and bivalent, MZ1 16 and MZ2 16 (which differ by one PEG unit in the linker) BET degraders as scaffolds, all of which have 15, 11 and 14 C/O atoms, respectively, between the terminal amide NH of VH032 and JQ1 (Figure ). To enable CRBN mediated degradation of BET proteins, we chose to use the scaffold of dBET54, 17 an active CRBN recruiting BET degrader comprising of a 20 C/O atom long linker between the ether O tether to thalidomide and the amide NH of JQ1. Lastly, to avoid E3 ligase crossdegradation, we opted to use the linker lengths of inactive/poor CRBN-VHL heterobifunctional-E3 ligase degraders, "Compounds 7a & 7b", 18 ZXH-4-135, 19 CRBN-2-2-2-2-VHL, 20 and CRBN-2-2-2-5-VHL, 20 /O/N atoms, respectively, between VH032 amide NH, and the aniline NH tether to thalidomide) (Figure ).