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Structure-Based Design of Potent and Orally Active Isoindolinone Inhibitors of MDM2-p53 Protein–Protein Interaction

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    Structure-Based Design of Potent and Orally Active Isoindolinone Inhibitors of MDM2-p53 Protein–Protein Interaction
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    Other Access OptionsSupporting Information (4)

    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2021, 64, 7, 4071–4088
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    https://doi.org/10.1021/acs.jmedchem.0c02188
    Published March 24, 2021
    Copyright © 2021 American Chemical Society
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    Abstract

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    Inhibition of murine double minute 2 (MDM2)-p53 protein–protein interaction with small molecules has been shown to reactivate p53 and inhibit tumor growth. Here, we describe rational, structure-guided, design of novel isoindolinone-based MDM2 inhibitors. MDM2 X-ray crystallography, quantum mechanics ligand-based design, and metabolite identification all contributed toward the discovery of potent in vitro and in vivo inhibitors of the MDM2-p53 interaction with representative compounds inducing cytostasis in an SJSA-1 osteosarcoma xenograft model following once-daily oral administration.

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c02188.

    • Molecular formula string (CSV)

    • Model of the X-ray crystal structure of MDM2 with compound 4 (CIF)

    • Structure factors of the X-ray crystal structure of MDM2 with compound 4 (CIF)

    • Additional experimental details for compounds not included in the main section and analytical data for all compounds and intermediates; NMR studies on 5; X-ray structure tables; and computational chemistry (PDF)

    Accession Codes

    Coordinates for MDM2 complexes with compounds 1, 5, 13, 14, and 23 have been deposited in the Protein Data Bank (PDB) under accession codes 7BJ0, 7BMG, 7BJ6, 7BIV, and 7BIR, respectively. Coordinates for the small molecule crystal structure of compound 18 have been deposited in the CCDC/FIZ Karlsruhe database under the deposition number 2059877.

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    Cite this: J. Med. Chem. 2021, 64, 7, 4071–4088
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    https://doi.org/10.1021/acs.jmedchem.0c02188
    Published March 24, 2021
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