• Open Access

Small-Molecule Proteomimetic Inhibitors of the HIF-1α–p300 Protein–Protein Interaction

Authors

  • George M. Burslem,

    1. School of Chemistry, University of Leeds, Woodhouse Lane, Leeds LS2 9JT (UK)
    2. Astbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT (UK)
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  • Hannah F. Kyle,

    1. Astbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT (UK)
    2. School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Woodhouse Lane, Leeds LS2 9JT (UK)
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  • Dr. Alexander L. Breeze,

    1. Protein Structure and Biophysics, Discovery Sciences, AstraZeneca R&D, Alderley Park, Cheshire, SK10 4TG (UK)
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  • Dr. Thomas A. Edwards,

    1. Astbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT (UK)
    2. School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Woodhouse Lane, Leeds LS2 9JT (UK)
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  • Prof. Adam Nelson,

    1. School of Chemistry, University of Leeds, Woodhouse Lane, Leeds LS2 9JT (UK)
    2. Astbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT (UK)
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  • Dr. Stuart L. Warriner,

    1. School of Chemistry, University of Leeds, Woodhouse Lane, Leeds LS2 9JT (UK)
    2. Astbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT (UK)
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  • Prof. Andrew J. Wilson

    Corresponding author
    1. School of Chemistry, University of Leeds, Woodhouse Lane, Leeds LS2 9JT (UK)
    2. Astbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT (UK)
    • School of Chemistry, University of Leeds, Woodhouse Lane, Leeds LS2 9JT (UK)===

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Abstract

The therapeutically relevant hypoxia inducible factor HIF-1α–p300 protein–protein interaction can be orthosterically inhibited with α-helix mimetics based on an oligoamide scaffold that recapitulates essential features of the C-terminal helix of the HIF-1α C-TAD (C-terminal transactivation domain). Preliminary SAR studies demonstrated the important role of side-chain size and hydrophobicity/hydrophilicity in determining potency. These small molecules represent the first biophysically characterised HIF-1α–p300 PPI inhibitors and the first examples of small-molecule aromatic oligoamide helix mimetics to be shown to have a selective binding profile. Although the compounds were less potent than HIF-1α, the result is still remarkable in that the mimetic reproduces only three residues from the 42-residue HIF-1α C-TAD from which it is derived.

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