Modulating FOXO3 transcriptional activity by small, DBD-binding molecules
- Medical University Innsbruck, Austria
- The Czech Academy of Sciences, Czech Republic
- University of Innsbruck, Austria
- Charles University, Czech Republic
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.
Data availability
All data generated or analyzed during this study are included in manuscript and supporting files.
Article and author information
Author details
Katarina Psenakova
Michael J Ausserlechner
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
- Xavier Darzacq, University of California, Berkeley, United States
Publication history
- Received: May 29, 2019
- Accepted: December 1, 2019
- Accepted Manuscript published: December 2, 2019 (version 1)
- Accepted Manuscript updated: December 4, 2019 (version 2)
- Version of Record published: December 18, 2019 (version 3)
- 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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Modulating FOXO3 transcriptional activity by small, DBD-binding molecules
eLife 8:e48876.
https://doi.org/10.7554/eLife.48876
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