2. Academic Validation
  3. Modulating FOXO3 transcriptional activity by small, DBD-binding molecules

Modulating FOXO3 transcriptional activity by small, DBD-binding molecules

  • Elife. 2019 Dec 4:8:e48876. doi: 10.7554/eLife.48876.
Judith Hagenbuchner # 1,  Veronika Obsilova # 2,  Teresa Kaserer # 3 4 5,  Nora Kaiser 4,  Bettina Rass 4,  Katarina Psenakova 2 6,  Vojtech Docekal 7,  Miroslava Alblova 2,  Klara Kohoutova 2 6,  Daniela Schuster 3 8,  Tatsiana Aneichyk 9 10,  Jan Vesely 7,  Petra Obexer 1 5,  Tomas Obsil 2 6,  Michael J Ausserlechner 4
Affiliations

Affiliations

  • 1 Department of Pediatrics II, Medical University Innsbruck, Innsbruck, Austria.
  • 2 Department of Structural Biology of Signaling Proteins, Institute of Physiology, Division BIOCEV, The Czech Academy of Sciences, Prague, Czech Republic.
  • 3 Pharmaceutical Chemistry, Institute of Pharmacy, University of Innsbruck, Innsbruck, Austria.
  • 4 Department of Pediatrics I, Medical University Innsbruck, Innsbruck, Austria.
  • 5 Tyrolean Cancer Research Institute, Innsbruck, Austria.
  • 6 Department of Physical and Macromolecular Chemistry, Faculty of Science, Charles University, Prague, Czech Republic.
  • 7 Department of Organic Chemistry, Faculty of Science, Charles University, Prague, Czech Republic.
  • 8 Department of Pharmaceutical and Medicinal Chemistry, Paracelsus Medical University Salzburg, Salzburg, Austria.
  • 9 Division of Molecular Pathophysiology, Biocenter, Medical University Innsbruck, Innsbruck, Austria.
  • 10 Independent Data Lab UG, Munich, Germany.
  • # Contributed equally.
PMID: 31789593 DOI: 10.7554/eLife.48876
Abstract

FOXO transcription factors are critical regulators of cell homeostasis and steer cell death, differentiation and longevity in mammalian cells. By combined pharmacophore-modeling-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.

Keywords

FOXO transcription factors; biochemistry; cancer biology; chemical biology; docking; drug targeting; human; molecular biophysics; pharmacophore modelling; small compounds; structural biology.

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