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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,
Biology and Bio-materials
Instruments:
I04-1-Macromolecular Crystallography (fixed wavelength)
Added On:
04/09/2017 10:06
Documents:
acs.jmedc56hem.pdf
Discipline Tags:
Non-Communicable Diseases
Health & Wellbeing
Cancer
Biochemistry
Chemistry
Structural biology
Organic Chemistry
Drug Discovery
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)