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Discovery of Small Compounds that Target FOXO Transcription Factors and Modulate their Transcriptional Activity and Physiological Function

The result's identifiers

  • Result code in IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F21%3A00550965" target="_blank" >RIV/67985823:_____/21:00550965 - isvavai.cz</a>

  • Result on the web

    <a href="https://doi.org/10.9734/bpi/nicb/v4/14349D" target="_blank" >https://doi.org/10.9734/bpi/nicb/v4/14349D</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.9734/bpi/nicb/v4/14349D" target="_blank" >10.9734/bpi/nicb/v4/14349D</a>

Alternative languages

  • Result language

    angličtina

  • Original language name

    Discovery of Small Compounds that Target FOXO Transcription Factors and Modulate their Transcriptional Activity and Physiological Function

  • Original language description

    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.

  • Czech name

  • Czech description

Classification

  • Type

    C - Chapter in a specialist book

  • CEP classification

  • OECD FORD branch

    10608 - Biochemistry and molecular biology

Result continuities

  • Project

  • Continuities

    I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Others

  • Publication year

    2021

  • Confidentiality

    S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Data specific for result type

  • Book/collection name

    New Innovations in Chemistry and Biochemistry

  • ISBN

    978-93-5547-113-0

  • Number of pages of the result

    14

  • Pages from-to

    41-54

  • Number of pages of the book

    136

  • Publisher name

    B P International

  • Place of publication

    Hoogly

  • UT code for WoS chapter