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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 (Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee) , Morgan Gadd (Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee) , Pedro Soares (Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee) , Salvatore Scaffidi (Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee) , Inge Van Molle (Department of Chemistry, University of Cambridge) , Ipek Birced (Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee) , Sarah Hewitt (Department of Chemistry, University of Cambridge) , David M. Dias (Department of Chemistry, University of Cambridge) , Alessio Ciulli (Division of Biological Chemistry and Drug Discovery, College of Life Sciences, 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.

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


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Other Facilities: ESRF (ID14-4 and BM14)

Documents:
jm5011258-1.pdf