Abstract

FOXO transcription factors are critical regulators of cell homeostasis and steer cell death, differentiation and longevity in mammalian cells. By combined pharmacophore-modelling-based in silico and fluorescence polarization-based screening we identified small molecules that physically interact with the DNA-binding domain (DBD) of FOXO3 and modulate the FOXO3 transcriptional program in human cells. The mode of interaction between compounds and the FOXO3-DBD was assessed via NMR spectroscopy and docking studies. We demonstrate that compounds S9 and its oxalate salt S9OX interfere with FOXO3 target promoter binding, gene transcription and modulate the physiologic program activated by FOXO3 in cancer cells. These small molecules prove the druggability of the FOXO-DBD and provide a structural basis for modulating these important homeostasis regulators in normal and malignant cells.

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All data generated or analyzed during this study are included in manuscript and supporting files.

Article and author information

Author details

  1. Judith Hagenbuchner

    Department of Pediatrics II, Medical University Innsbruck, Innsbruck, Austria
    Competing interests
    The authors declare that no competing interests exist.
  2. Veronika Obsilova

    Department of Structural Biology of Signaling Proteins, The Czech Academy of Sciences, Prague, Czech Republic
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4887-0323
  3. Teresa Kaserer

    Institute of Pharmacy, University of Innsbruck, Innsbruck, Austria
    Competing interests
    The authors declare that no competing interests exist.
  4. Nora Kaiser

    Department of Pediatrics I, Medical University Innsbruck, Innsbruck, Austria
    Competing interests
    The authors declare that no competing interests exist.
  5. Bettina Rass

    Department of Pediatrics I, Medical University Innsbruck, Innsbruck, Austria
    Competing interests
    The authors declare that no competing interests exist.
  6. Katarina Psenakova

    Department of Structural Biology of Signaling Proteins, The Czech Academy of Sciences, Prague, Czech Republic
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8877-6599
  7. Vojtech Docekal

    Department of Organic Chemistry, Charles University, Prague, Czech Republic
    Competing interests
    The authors declare that no competing interests exist.
  8. Miroslava Alblova

    Department of Structural Biology of Signaling Proteins, The Czech Academy of Sciences, Prague, Czech Republic
    Competing interests
    The authors declare that no competing interests exist.
  9. Klara Kohoutova

    Department of Structural Biology of Signaling Proteins, The Czech Academy of Sciences, Prague, Czech Republic
    Competing interests
    The authors declare that no competing interests exist.
  10. Daniela Schuster

    Institute of Pharmacy, University of Innsbruck, Innsbruck, Austria
    Competing interests
    The authors declare that no competing interests exist.
  11. Tatsiana Aneichyk

    Division of Molecular Pathophysiology, Medical University Innsbruck, Innsbruck, Austria
    Competing interests
    The authors declare that no competing interests exist.
  12. Jan Vesely

    Department of Organic Chemistry, Charles University, Prague, Czech Republic
    Competing interests
    The authors declare that no competing interests exist.
  13. Petra Obexer

    Department of Pediatrics II, Medical University Innsbruck, Innsbruck, Austria
    Competing interests
    The authors declare that no competing interests exist.
  14. Tomas Obsil

    Department of Structural Biology of Signaling Proteins, The Czech Academy of Sciences, Prague, Czech Republic
    For correspondence
    obsil@natur.cuni.cz
    Competing interests
    The authors declare that no competing interests exist.
  15. Michael J Ausserlechner

    Department of Pediatrics I, Medical University Innsbruck, Innsbruck, Austria
    For correspondence
    michael.j.ausserlechner@i-med.ac.at
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1015-2302

Funding

Austrian Science Fund (I3089-B28)

  • Judith Hagenbuchner
  • Veronika Obsilova
  • Tomas Obsil
  • Michael J Ausserlechner

Grantová Agentura České Republiky (17-33854L)

  • Veronika Obsilova
  • Tomas Obsil

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Xavier Darzacq, University of California, Berkeley, United States

Version history

  1. Received: May 29, 2019
  2. Accepted: December 1, 2019
  3. Accepted Manuscript published: December 2, 2019 (version 1)
  4. Accepted Manuscript updated: December 4, 2019 (version 2)
  5. Version of Record published: December 18, 2019 (version 3)
  6. Version of Record updated: January 15, 2020 (version 4)

Copyright

© 2019, Hagenbuchner et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Judith Hagenbuchner
  2. Veronika Obsilova
  3. Teresa Kaserer
  4. Nora Kaiser
  5. Bettina Rass
  6. Katarina Psenakova
  7. Vojtech Docekal
  8. Miroslava Alblova
  9. Klara Kohoutova
  10. Daniela Schuster
  11. Tatsiana Aneichyk
  12. Jan Vesely
  13. Petra Obexer
  14. Tomas Obsil
  15. Michael J Ausserlechner
(2019)
Modulating FOXO3 transcriptional activity by small, DBD-binding molecules
eLife 8:e48876.
https://doi.org/10.7554/eLife.48876

Share this article

https://doi.org/10.7554/eLife.48876

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