laboratory in Brd9 degrader VZ185; 3) via a thioether linkage out of the tert-butyl group of the VHL ligand, in which the tert-Leu group is replaced with a penicillamine group, as we previously incorporated in Brd4-selective degrader AT1. Unlike AT1, in which the VHL ligand handle bears a terminal acetyl group, here we decided to keep the terminal fluorocyclopropyl group as in VH101. As CRBN handle, we chose pomalidomide because of its greater cellular stability compared to other ImIds. To derivatize pomalidomide we appended an ethylenediamine spacer out of the phthalimide ring (compound 3, Figure ), to provide a synthetically convenient attachment point for amide conjugation of a linker. The linker plays a crucial role in PROTAC design and activity. Small changes in both length and physicochemical nature e.g. alkylic versus polyethylene glycol (PEG) as well as mixtures thereof, are known to impact degradation activity and selectivity in often unpredictable ways. We therefore decided to explore different linkers, focusing on varying lengths and ratio between carbon and oxygen atoms, as we and others have found that these modifications can have a profound impact on PROTAC structure-activity relationships. As a result, the designed compounds explore diversity in the derivatization point, linker length and chemical properties.