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Highly selective inhibition of histone demethylases by de novo macrocyclic peptides

Author

Listed:
  • Akane Kawamura

    (Chemistry Research Laboratory, University of Oxford
    Wellcome Trust Centre for Human Genetics)

  • Martin Münzel

    (Chemistry Research Laboratory, University of Oxford
    Present address: Novo Nordisk A/S, Novo Nordisk Park, 2760 Måløv, Denmark)

  • Tatsuya Kojima

    (Graduate School of Science, The University of Tokyo)

  • Clarence Yapp

    (Structural Genomics Consortium, University of Oxford
    Target Discovery Institute, University of Oxford)

  • Bhaskar Bhushan

    (Chemistry Research Laboratory, University of Oxford
    Wellcome Trust Centre for Human Genetics)

  • Yuki Goto

    (Graduate School of Science, The University of Tokyo)

  • Anthony Tumber

    (Structural Genomics Consortium, University of Oxford
    Target Discovery Institute, University of Oxford)

  • Takayuki Katoh

    (Graduate School of Science, The University of Tokyo)

  • Oliver N. F. King

    (Chemistry Research Laboratory, University of Oxford)

  • Toby Passioura

    (Graduate School of Science, The University of Tokyo)

  • Louise J. Walport

    (Chemistry Research Laboratory, University of Oxford)

  • Stephanie B. Hatch

    (Structural Genomics Consortium, University of Oxford
    Target Discovery Institute, University of Oxford)

  • Sarah Madden

    (Chemistry Research Laboratory, University of Oxford)

  • Susanne Müller

    (Structural Genomics Consortium, University of Oxford
    Target Discovery Institute, University of Oxford
    Present address: Structural Genomics Consortium, Goethe Universität Frankfurt, Buchmann Institute for Molecular Life Sciences, Riedberg Campus, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany.)

  • Paul E. Brennan

    (Structural Genomics Consortium, University of Oxford
    Target Discovery Institute, University of Oxford)

  • Rasheduzzaman Chowdhury

    (Chemistry Research Laboratory, University of Oxford)

  • Richard J. Hopkinson

    (Chemistry Research Laboratory, University of Oxford)

  • Hiroaki Suga

    (Graduate School of Science, The University of Tokyo
    JST, CREST)

  • Christopher J. Schofield

    (Chemistry Research Laboratory, University of Oxford)

Abstract

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 N-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.

Suggested Citation

  • Akane Kawamura & Martin Münzel & Tatsuya Kojima & Clarence Yapp & Bhaskar Bhushan & Yuki Goto & Anthony Tumber & Takayuki Katoh & Oliver N. F. King & Toby Passioura & Louise J. Walport & Stephanie B. , 2017. "Highly selective inhibition of histone demethylases by de novo macrocyclic peptides," Nature Communications, Nature, vol. 8(1), pages 1-10, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14773
    DOI: 10.1038/ncomms14773
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