Understanding Small-Molecule Binding to MDM2: Insights into Structural Effects of Isoindolinone Inhibitors from NMR Spectroscopy

Authors

  • Christiane Riedinger,

    1. Laboratory of Molecular Biophysics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
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  • Martin E. Noble,

    1. Laboratory of Molecular Biophysics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
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  • David J. Wright,

    1. Laboratory of Molecular Biophysics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
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  • Florian Mulks,

    1. Laboratory of Molecular Biophysics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
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  • Ian R. Hardcastle,

    1. Northern Institute for Cancer Research, Bedson Building, University of Newcastle, Newcastle NE1 4RW, UK
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  • Jane A. Endicott,

    1. Laboratory of Molecular Biophysics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
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  • James M. McDonnell

    Corresponding author
    1. Laboratory of Molecular Biophysics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
    2. The Randall Division of Cell & Molecular Biophysics, King’s College London, Guy’s Campus, London SE1 1UL, UK
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Corresponding author: James M. McDonnell; james.mcdonnell@kcl.ac.uk

Abstract

The interaction between murine double minute (MDM2) and p53 is a major target in anticancer drug design. Several potent compound series, including the nutlins and spirooxindoles, have previously been established as high-affinity antagonists of MDM2. In this paper, we describe the interaction of isoindolinone inhibitors with MDM2, as characterized by nuclear magnetic resonance spectroscopy. Isoindolinone inhibitors bind specifically to the MDM2 p53 binding site and exploit all sub-pockets used by p53, nutlins and spirooxindoles. Furthermore, isoindolinones bind with low micromolar to high nanomolar affinities, with the best compound approaching the potency of nutlin-3.

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