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Structure-guided design of a selective inhibitor of the methyltransferase KMT9 with cellular activity

Author

Listed:
  • Sheng Wang

    (Klinikum der Albert-Ludwigs-Universität Freiburg)

  • Sebastian O. Klein

    (University of Freiburg)

  • Sylvia Urban

    (Klinikum der Albert-Ludwigs-Universität Freiburg)

  • Maximilian Staudt

    (Albert-Ludwigs-Universität Freiburg)

  • Nicolas P. F. Barthes

    (Albert-Ludwigs-Universität Freiburg)

  • Dominica Willmann

    (Klinikum der Albert-Ludwigs-Universität Freiburg)

  • Johannes Bacher

    (Albert-Ludwigs-Universität Freiburg)

  • Manuela Sum

    (Klinikum der Albert-Ludwigs-Universität Freiburg)

  • Helena Bauer

    (Klinikum der Albert-Ludwigs-Universität Freiburg)

  • Ling Peng

    (Klinikum der Albert-Ludwigs-Universität Freiburg)

  • Georg A. Rennar

    (Albert-Ludwigs-Universität Freiburg)

  • Christian Gratzke

    (Klinikum der Albert-Ludwigs-Universität Freiburg)

  • Katrin M. Schüle

    (Faculty of Medicine, University of Freiburg)

  • Lin Zhang

    (Albert-Ludwigs-Universität Freiburg)

  • Oliver Einsle

    (Albert-Ludwigs-Universität Freiburg)

  • Holger Greschik

    (Klinikum der Albert-Ludwigs-Universität Freiburg)

  • Calum MacLeod

    (Drug Discovery, Pharmaron UK Ltd)

  • Christopher G. Thomson

    (Drug Discovery, Pharmaron UK Ltd)

  • Manfred Jung

    (University of Freiburg
    Albert-Ludwigs-Universität Freiburg
    Deutsches Konsortium für Translationale Krebsforschung, Standort Freiburg)

  • Eric Metzger

    (Klinikum der Albert-Ludwigs-Universität Freiburg
    Deutsches Konsortium für Translationale Krebsforschung, Standort Freiburg)

  • Roland Schüle

    (Klinikum der Albert-Ludwigs-Universität Freiburg
    University of Freiburg
    Deutsches Konsortium für Translationale Krebsforschung, Standort Freiburg)

Abstract

Inhibition of epigenetic regulators by small molecules is an attractive strategy for cancer treatment. Recently, we characterised the role of lysine methyltransferase 9 (KMT9) in prostate, lung, and colon cancer. Our observation that the enzymatic activity was required for tumour cell proliferation identified KMT9 as a potential therapeutic target. Here, we report the development of a potent and selective KMT9 inhibitor (compound 4, KMI169) with cellular activity through structure-based drug design. KMI169 functions as a bi-substrate inhibitor targeting the SAM and substrate binding pockets of KMT9 and exhibits high potency, selectivity, and cellular target engagement. KMT9 inhibition selectively downregulates target genes involved in cell cycle regulation and impairs proliferation of tumours cells including castration- and enzalutamide-resistant prostate cancer cells. KMI169 represents a valuable tool to probe cellular KMT9 functions and paves the way for the development of clinical candidate inhibitors as therapeutic options to treat malignancies such as therapy-resistant prostate cancer.

Suggested Citation

  • Sheng Wang & Sebastian O. Klein & Sylvia Urban & Maximilian Staudt & Nicolas P. F. Barthes & Dominica Willmann & Johannes Bacher & Manuela Sum & Helena Bauer & Ling Peng & Georg A. Rennar & Christian , 2024. "Structure-guided design of a selective inhibitor of the methyltransferase KMT9 with cellular activity," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44243-6
    DOI: 10.1038/s41467-023-44243-6
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    References listed on IDEAS

    as
    1. Paz Polak & Rosa Karlić & Amnon Koren & Robert Thurman & Richard Sandstrom & Michael S. Lawrence & Alex Reynolds & Eric Rynes & Kristian Vlahoviček & John A. Stamatoyannopoulos & Shamil R. Sunyaev, 2015. "Cell-of-origin chromatin organization shapes the mutational landscape of cancer," Nature, Nature, vol. 518(7539), pages 360-364, February.
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