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Modulating FOXO3 transcriptional activity by small, DBD-binding molecules

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...

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Autores principales: Hagenbuchner, Judith, Obsilova, Veronika, Kaserer, Teresa, Kaiser, Nora, Rass, Bettina, Psenakova, Katarina, Docekal, Vojtech, Alblova, Miroslava, Kohoutova, Klara, Schuster, Daniela, Aneichyk, Tatsiana, Vesely, Jan, Obexer, Petra, Obsil, Tomas, Ausserlechner, Michael J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6919977/
https://www.ncbi.nlm.nih.gov/pubmed/31789593
http://dx.doi.org/10.7554/eLife.48876
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author Hagenbuchner, Judith
Obsilova, Veronika
Kaserer, Teresa
Kaiser, Nora
Rass, Bettina
Psenakova, Katarina
Docekal, Vojtech
Alblova, Miroslava
Kohoutova, Klara
Schuster, Daniela
Aneichyk, Tatsiana
Vesely, Jan
Obexer, Petra
Obsil, Tomas
Ausserlechner, Michael J
author_facet Hagenbuchner, Judith
Obsilova, Veronika
Kaserer, Teresa
Kaiser, Nora
Rass, Bettina
Psenakova, Katarina
Docekal, Vojtech
Alblova, Miroslava
Kohoutova, Klara
Schuster, Daniela
Aneichyk, Tatsiana
Vesely, Jan
Obexer, Petra
Obsil, Tomas
Ausserlechner, Michael J
author_sort Hagenbuchner, Judith
collection PubMed
description 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.
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spelling pubmed-69199772019-12-19 Modulating FOXO3 transcriptional activity by small, DBD-binding molecules Hagenbuchner, Judith Obsilova, Veronika Kaserer, Teresa Kaiser, Nora Rass, Bettina Psenakova, Katarina Docekal, Vojtech Alblova, Miroslava Kohoutova, Klara Schuster, Daniela Aneichyk, Tatsiana Vesely, Jan Obexer, Petra Obsil, Tomas Ausserlechner, Michael J eLife Biochemistry and Chemical Biology 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. eLife Sciences Publications, Ltd 2019-12-04 /pmc/articles/PMC6919977/ /pubmed/31789593 http://dx.doi.org/10.7554/eLife.48876 Text en © 2019, Hagenbuchner et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Biochemistry and Chemical Biology
Hagenbuchner, Judith
Obsilova, Veronika
Kaserer, Teresa
Kaiser, Nora
Rass, Bettina
Psenakova, Katarina
Docekal, Vojtech
Alblova, Miroslava
Kohoutova, Klara
Schuster, Daniela
Aneichyk, Tatsiana
Vesely, Jan
Obexer, Petra
Obsil, Tomas
Ausserlechner, Michael J
Modulating FOXO3 transcriptional activity by small, DBD-binding molecules
title Modulating FOXO3 transcriptional activity by small, DBD-binding molecules
title_full Modulating FOXO3 transcriptional activity by small, DBD-binding molecules
title_fullStr Modulating FOXO3 transcriptional activity by small, DBD-binding molecules
title_full_unstemmed Modulating FOXO3 transcriptional activity by small, DBD-binding molecules
title_short Modulating FOXO3 transcriptional activity by small, DBD-binding molecules
title_sort modulating foxo3 transcriptional activity by small, dbd-binding molecules
topic Biochemistry and Chemical Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6919977/
https://www.ncbi.nlm.nih.gov/pubmed/31789593
http://dx.doi.org/10.7554/eLife.48876
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