Group-based optimization of potent and cell-active inhibitors of the von Hippel-Lindau (VHL) E3 ubiquitin ligase

DOI: 10.1021/acs.jmedchem.7b00675

Authors: Pedro Soares (University of Dundee) , Morgan S. Gadd (University of Dundee) , Julianty Frost (University of Dundee) , Carles Galdeano (University of Dundee) , Lucy C. J. Ellis (University of Dundee) , Ola Epemolu (University of Dundee) , Sonia Rocha (University of Dundee) , Kevin D. Read (University of Dundee) , Alessio Ciulli (University of Dundee)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: August 2017
Diamond Proposal Number(s): 10071

Abstract: 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 degradation. VHL is a potential target for treating anemia and ischemic diseases, motivating the development of inhibitors of the VHL:HIF-α protein-protein interaction. Additionally, bifunctional proteolysis targeting chimeras (PROTACs) containing a VHL ligand can hijack the E3 ligase activity to induce degradation 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 chemical probe VH298, with dissociation constants <100 nM, which induced marked HIF-1α intracellular stabilization. Our study provides new chemical tools to probe the VHL-HIF pathways, and new VHL ligands for next-generation PROTACs.

Subject Areas: Chemistry, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

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