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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Crystallography, X-Ray
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Ligands
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Models, Molecular
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Molecular Targeted Therapy
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Protein Binding
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Small Molecule Libraries / chemistry*
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Small Molecule Libraries / pharmacology*
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Structure-Activity Relationship
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Von Hippel-Lindau Tumor Suppressor Protein / chemistry
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Von Hippel-Lindau Tumor Suppressor Protein / metabolism*
Substances
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Ligands
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Small Molecule Libraries
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Von Hippel-Lindau Tumor Suppressor Protein
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VHL protein, human
Associated data
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PDB/4W9C
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PDB/4W9D
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PDB/4W9E
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PDB/4W9F
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PDB/4W9G
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PDB/4W9H
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PDB/4W9I
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PDB/4W9J
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PDB/4W9K
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PDB/4W9L