A first strategy to help improve our initial compounds, 1 and 2, was to switch from an amide linkage for JQ1 conjugation chemistry to an ester, a modification which we have previously shown to be beneficial when optimising JQ1-based BET degraders. 27, 28 Next, we chose to introduce diversity in the VHL binding ligand by adding a methyl group to the benzylic position of VH032, a modification that is known to enhance the binary binding affinity to VHL. 27-29 To gain a better understanding of the effects on linker length between each ligand, we decided to synthesise analogues which varied in the number of PEG units separating either JQ1 or thalidomide to the central quaternary carbon centre of the linker (Table ). Finally, we wanted to vary the linker attachment vector and functionality to thalidomide. Additionally to the anilines tethered at the 4-C of the phthalimide, we sought to use another linkage vector at the 5-C, a tethering site which has been used