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Small-Molecule Inhibitors of the Interaction between the E3 Ligase VHL and HIF1α

Authors

  • Dennis L. Buckley,

    1. Departments of Chemistry, Molecular, Cellular & Developmental Biology and Pharmacology and Center for Molecular Discovery, Yale University, New Haven, CT 06511 (USA)
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  • Dr. Jeffrey L. Gustafson,

    1. Departments of Chemistry, Molecular, Cellular & Developmental Biology and Pharmacology and Center for Molecular Discovery, Yale University, New Haven, CT 06511 (USA)
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  • Dr. Inge Van Molle,

    1. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW (UK)
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  • Dr. Anke G. Roth,

    1. Departments of Chemistry, Molecular, Cellular & Developmental Biology and Pharmacology and Center for Molecular Discovery, Yale University, New Haven, CT 06511 (USA)
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  • Dr. Hyun Seop Tae,

    1. Departments of Chemistry, Molecular, Cellular & Developmental Biology and Pharmacology and Center for Molecular Discovery, Yale University, New Haven, CT 06511 (USA)
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  • Dr. Peter C. Gareiss,

    1. Departments of Chemistry, Molecular, Cellular & Developmental Biology and Pharmacology and Center for Molecular Discovery, Yale University, New Haven, CT 06511 (USA)
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  • Prof. William L. Jorgensen,

    1. Departments of Chemistry, Molecular, Cellular & Developmental Biology and Pharmacology and Center for Molecular Discovery, Yale University, New Haven, CT 06511 (USA)
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  • Dr. Alessio Ciulli,

    1. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW (UK)
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  • Prof. Craig M. Crews

    Corresponding author
    1. Departments of Chemistry, Molecular, Cellular & Developmental Biology and Pharmacology and Center for Molecular Discovery, Yale University, New Haven, CT 06511 (USA)
    • Departments of Chemistry, Molecular, Cellular & Developmental Biology and Pharmacology and Center for Molecular Discovery, Yale University, New Haven, CT 06511 (USA)
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  • This research was supported in part by the NIH (AI084140, GM032136), BBSRC (BB/G023123/1), and EC (PIEF-GA-2010-275683). J.L.G. thanks the NIH for a postdoctoral fellowship (F32GM10052101). A.G.R. is a Leopoldina-Nationale Akademie der Wissenschaften Postdoctoral Fellow. We are grateful to the beamline scientists of the Proxima-1 beamline at the Soleil synchrotron facility for their assistance.

Abstract

original image

By design: Novel small-molecule inhibitors of the interaction between the von Hippel–Lindau ligase (VHL) and its molecular target HIF1α, a transcription factor involved in oxygen sensing, have been developed and studied. The most potent inhibitor binds with an IC50 value of 0.9 μM and is thus the first sub-micromolar inhibitor of the VHL–HIF1α interaction.

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