Impact of Linker\nComposition on VHL PROTAC Cell Permeability

The discovery of\ncell permeable and orally bioavailable von Hippel-Lindau\n(VHL) proteolysis targeting chimeras (PROTACs) is challenging as their\nstructures locates them at, or beyond, the outer limits of oral druggable\nspace. We have designed a set of nine VHL PROTACs and found that the\nlinker had a profound impact on passive cell permeability. Determination\nof the solution ensembles in a nonpolar solvent revealed that high\npermeability was correlated to the ability of the PROTACs to adopt\nfolded conformations that have a low solvent accessible 3D polar surface\narea. Our results suggest that the design of cell permeable VHL PROTACs\ncould focus on linkers that facilitate shielding of polar surface\narea in the VHL ligand in a nonpolar but not in a polar environment.\nIn addition, we found that not only intramolecular hydrogen bonds,\nbut also NH–π and π–π interactions\ncontribute to the stabilization of low-polarity conformations, and\nthereby to high cell permeability.