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30 Aug 2017

The von Hippel-​Lindau tumor suppressor protein is the substrate binding subunit of the VHL E3 ubiquitin ligase, which targets hydroxylated α subunit of hypoxia inducible factors (HIFs) for ubiquitination and subsequent proteasomal degrdn.  VHL is a potential target for treating anemia and ischemic diseases, motivating the development of inhibitors of the VHL:HIF-​α protein-​protein interaction.  Addnl., bifunctional proteolysis targeting chimeras (PROTACs) contg. a VHL ligand can hijack the E3 ligase activity to induce degrdn. of target proteins.  We report the structure-​guided design and group-​based optimization of a series of VHL inhibitors with low nanomolar potencies and improved cellular permeability.  Structure-​activity relationships led to the discovery of potent inhibitors 10 and chem. probe VH298, with dissocn. consts. <100 nM, which induced marked HIF-​1α intracellular stabilization.  Our study provides new chem. tools to probe the VHL-​HIF pathways and new VHL ligands for next-​generation PROTACs.