Abstact

von Hippel-Lindau (VHL) is an E3 ligase that has been widely exploited for the development of PROTACs to induce degradation of disease-associated target proteins. Nearly all VHL-recruiting PROTACs contain a hydroxyproline moiety based on the endogenous peptide substrate that occupies the HIF1α-binding site of VHL. However, the development of orally bioavailable PROTACs with hydroxyproline-based VHL ligands remains a significant hurdle, due to both the hydroxyproline and the peptidic nature of the VHL ligand. Here, we describe an NMR-based fragment screen against the VHL-Elongin C-Elongin B (VCB) complex. Several hits were shown by X-ray crystallography to bind to the HIF1α active site in VHL of the VCB complex, which opens the possibility for the discovery of new nonhydroxyproline-based VHL ligands for use in VHL-recruiting PROTACs.