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

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

C - Kapitola v odborné knize

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2021

Kód důvěrnosti údajů

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

Název knihy nebo sborníku

New Innovations in Chemistry and Biochemistry

ISBN

978-93-5547-113-0

Počet stran výsledku

14

Strana od-do

41-54

Počet stran knihy

136

Název nakladatele

B P International

Místo vydání

Hoogly

Kód UT WoS kapitoly

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