Modulating FOXO3 transcriptional activity by small, DBD-binding molecules

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F19%3A00518629" target="_blank" >RIV/67985823:_____/19:00518629 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11310/19:10402417

Výsledek na webu

<a href="https://elifesciences.org/articles/48876" target="_blank" >https://elifesciences.org/articles/48876</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.7554/eLife.48876" target="_blank" >10.7554/eLife.48876</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Modulating FOXO3 transcriptional activity by small, DBD-binding molecules

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

Modulating FOXO3 transcriptional activity by small, DBD-binding molecules

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

<a href="/cs/project/GF17-33854L" target="_blank" >GF17-33854L: Inhibice interakcí mezi FOXO3 a DNA pomocí nízkomolekulárních látek</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2019

Kód důvěrnosti údajů

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

Název periodika

eLife

ISSN

2050-084X

e-ISSN

—

Svazek periodika

8

Číslo periodika v rámci svazku

Dec 4

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

21

Strana od-do

e48876

Kód UT WoS článku

000503449700001

EID výsledku v databázi Scopus

2-s2.0-85076876862