In order to better explore potentially different relative orientations between the two E3 ligases, we began by designing three series of heterodimerizers characterized by different attachment points on the VHL ligase handle (Figure ): 1) out of the terminal acetyl group of VHL ligand VH032. Amidation of a terminal tert-Leu of the VHL ligand (compound 1, Figure ) is a widely-explored conjugation strategy for PROTACs, including our homo-PROTAC CM11; 2) via a phenolic substituent out of VH101, a more potent VHL ligand in which the cyano-cyclopropyl group of chemical probe VH298 is replaced with a fluorocyclopropyl group, as shown in our published SAR of VHL ligands. Successful conjugation of this optimized VHL ligand (compound 2, Figure ) was recently reported by our