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

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 degradatio...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2014-10, Vol.57 (20), p.8657-8663
Main Authors: Galdeano, Carles, Gadd, Morgan S, Soares, Pedro, Scaffidi, Salvatore, Van Molle, Inge, Birced, Ipek, Hewitt, Sarah, Dias, David M, Ciulli, Alessio
Format: Article
Language:English
Subjects:
Brief
Crystallography, X-Ray
Humans
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Ligands
Models, Molecular
Molecular Targeted Therapy
Protein Binding
Small Molecule Libraries - chemistry
Small Molecule Libraries - pharmacology
Structure-Activity Relationship
Von Hippel-Lindau Tumor Suppressor Protein - chemistry
Von Hippel-Lindau Tumor Suppressor Protein - metabolism
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm5011258