Impact of Linker Composition on VHL PROTAC Cell Permeability

The discovery of
cell permeable and orally bioavailable von Hippel-Lindau
(VHL) proteolysis targeting chimeras (PROTACs) is challenging as their
structures locates them at, or beyond, the outer limits of oral druggable
space. We have designed a set of nine VHL PROTACs and found that the
linker had a profound impact on passive cell permeability. Determination
of the solution ensembles in a nonpolar solvent revealed that high
permeability was correlated to the ability of the PROTACs to adopt
folded conformations that have a low solvent accessible 3D polar surface
area. Our results suggest that the design of cell permeable VHL PROTACs
could focus on linkers that facilitate shielding of polar surface
area in the VHL ligand in a nonpolar but not in a polar environment.
In addition, we found that not only intramolecular hydrogen bonds,
but also NH–π and π–π interactions
contribute to the stabilization of low-polarity conformations, and
thereby to high cell permeability.