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.
30 Aug 2017