Modulating FOXO3 Transcriptional Activity by Small, DBD-binding Molecules

Overview

Journal Elife

Specialty Biology

Date 2019 Dec 3

PMID 31789593

Citations 7

Authors

Judith Hagenbuchner

Veronika Obsilova

Teresa Kaserer

Nora Kaiser

Bettina Rass

Katarina Psenakova

Vojtech Docekal

Miroslava Alblova

Klara Kohoutova

Daniela Schuster

Tatsiana Aneichyk

Jan Vesely

Petra Obexer

Tomas Obsil

Michael J Ausserlechner

Affiliations

Soon will be listed here.

Abstract

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 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.

Citing Articles

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mTORC2 Is the Major Second Layer Kinase Negatively Regulating FOXO3 Activity.

Jimenez L, Amenabar C, Mayoral-Varo V, Mackenzie T, Ramos M, Silva A Molecules. 2022; 27(17).

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