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    • Highly selective inhibition of histone demethylases by de novo macrocyclic peptides

    DOI HANDLE HANDLE PDF Web Site ほか2件をすべて表示 一部だけ表示 研究データあり 被引用文献34件 参考文献43件 オープンアクセス

    書誌事項

    公開日
    2017-04-06
    資源種別
    journal article
    権利情報
    • https://creativecommons.org/licenses/by/4.0
    • https://creativecommons.org/licenses/by/4.0
    DOI
    • 10.1038/ncomms14773
    公開者
    Springer Science and Business Media LLC

    説明

    <jats:title>Abstract</jats:title><jats:p>The JmjC histone demethylases (KDMs) are linked to tumour cell proliferation and are current cancer targets; however, very few highly selective inhibitors for these are available. Here we report cyclic peptide inhibitors of the KDM4A-C with selectivity over other KDMs/2OG oxygenases, including closely related KDM4D/E isoforms. Crystal structures and biochemical analyses of one of the inhibitors (CP2) with KDM4A reveals that CP2 binds differently to, but competes with, histone substrates in the active site. Substitution of the active site binding arginine of CP2 to <jats:italic>N</jats:italic>-ɛ-trimethyl-lysine or methylated arginine results in cyclic peptide substrates, indicating that KDM4s may act on non-histone substrates. Targeted modifications to CP2 based on crystallographic and mass spectrometry analyses results in variants with greater proteolytic robustness. Peptide dosing in cells manifests KDM4A target stabilization. Although further development is required to optimize cellular activity, the results reveal the feasibility of highly selective non-metal chelating, substrate-competitive inhibitors of the JmjC KDMs.</jats:p>

    収録刊行物

    • Nature Communications

      Nature Communications 8 (1), 14773-, 2017-04-06

      Springer Science and Business Media LLC

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    参考文献 (43)*注記

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