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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...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2019
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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. |
format | Online Article Text |
id | pubmed-6919977 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
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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