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Structure-guided design and optimization of small molecules targeting the protein–protein interaction between the von Hippel–Lindau (VHL) E3 ubiquitin ligase and the Hypoxia Inducible Factor (HIF) alpha subunit with in vitro nanomolar affinities

DOI: 10.1021/jm5011258 DOI Help
PMID: 25166285 PMID Help

Authors: Carles Galdeano (University of Dundee) , Morgan Gadd (University of Dundee) , Pedro Soares (University of Dundee) , Salvatore Scaffidi (University of Dundee) , Inge Van Molle (University of Cambridge) , Ipek Birced (University of Dundee) , Sarah Hewitt (University of Cambridge) , David M. Dias (University of Cambridge) , Alessio Ciulli (University of Dundee)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 57 (20) , PAGES 8657 - 8663

State: Published (Approved)
Published: October 2014
Diamond Proposal Number(s): 8268

Open Access Open Access

Abstract: E3 ubiquitin ligases are attractive targets in the ubiquitin–proteasome system, however, the development of small-molecule ligands has been rewarded with limited success. The von Hippel–Lindau protein (pVHL) is the substrate recognition subunit of the VHL E3 ligase that targets HIF-1α for degradation. We recently reported inhibitors of the pVHL:HIF-1α interaction, however they exhibited moderate potency. Herein, we report the design and optimization, guided by X-ray crystal structures, of a ligand series with nanomolar binding affinities.

Journal Keywords: Crystal structure; Inhibitors; Ligands; Noncovalent interactions; Peptides and proteins

Subject Areas: Biology and Bio-materials, Medicine, Chemistry

Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Other Facilities: ID14-4, BM14 at ESRF

Added On: 24/02/2015 11:15


Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)