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New Innovations in Chemistry and Biochemistry

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    0550965 - FGÚ 2022 RIV IN eng M - Monography Chapter
    Hagenbuchner, J. - Obšilová, Veronika - Obexer, P. - Obšil, Tomáš - Ausserlechner, M. J.
    Discovery of Small Compounds that Target FOXO Transcription Factors and Modulate their Transcriptional Activity and Physiological Function.
    New Innovations in Chemistry and Biochemistry. Vol. 4. Hoogly: B P International, 2021 - (Romero Martínez, A.), s. 41-54. ISBN 978-93-5547-113-0
    Institutional support: RVO:67985823
    Keywords : drug-targeting * FOX proteins * FOXO transcription factors * small compounds
    OECD category: Biochemistry and molecular biology
    https://doi.org/10.9734/bpi/nicb/v4/14349D

    FOXO transcription factors are important cell homeostasis regulators that regulate a wide range of target genes, guiding cell death, differentiation, longevity, and senescence in mammalian cells. The goal of this research was to find new chemical compounds that attach to FOXO3’s DNA-binding domain and regulate its transcriptional activity. The plan was to combine in silico compound screening based on pharmacophore modelling with fluorescence polarisation protein-DNA binding tests and cell-based compound confirmation. Small compounds that physically interact with the DNA-binding domain (DBD) of FOXO transcription factors with the highest affinity for human FOXO3 were found using this method. These chemicals alter the FOXO3 transcriptional pathway in human cells rather than acting as pharmacologic inhibitors. NMR spectroscopy and docking experiments were used to determine the manner of interaction between drugs and the FOXO3-DBD. We show that substance S9 and its oxalate salt S9OX inhibit FOXO3 target promoter binding, modify gene transcription, and interfere with the physiological programme activated by FOXO3 in cancer cells. These tiny compounds demonstrate the druggability of the FOXO-DBD and give a structural basis for modifying these key homeostasis regulators in normal and malignant cells by directly changing protein-DNA interaction.
    Permanent Link: http://hdl.handle.net/11104/0326251

     
     
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