Table encompasses a variety of highly potent VHL ligands, all of which bear either hydrogen or fluorine in place of R . We suppose that sterically demanding substituents are not well tolerated at this position, as they might restrict the rotation about the aryl-aryl axis. To detail the binding mode of these high-affinity ligands, we paid attention to the orientation of their phenylene substituents. The R 1 methyl group of 24, the R 2 fluoro substituent of 32 and the R 3 methoxy group of 33 are solvent exposed. In contrast, the R 3 methyl group of 32 and the R 2 fluoro substituent of 33 are directed towards the protein.