Modulating FOXO3 transcriptional activity by small, DBD-binding molecules

0518629 - FGÚ 2020 RIV GB eng J - Journal Article
Hagenbuchner, J. - Obšilová, Veronika - Kaserer, T. - Kaiser, N. - Rass, B. - Pšenáková, Katarína - Dočekal, V. - Alblová, Miroslava - Kohoutová, Klára - Schuster, D. - Aneichyk, T. - Veselý, J. - Obexer, P. - Obšil, Tomáš - Ausserlechner, M. J.
Modulating FOXO3 transcriptional activity by small, DBD-binding molecules.
eLife. Roč. 8, Dec 4 (2019), č. článku e48876. ISSN 2050-084X. E-ISSN 2050-084X
R&D Projects: GA ČR(CZ) GF17-33854L
Institutional support: RVO:67985823
Keywords : small compounds * drug-targeting * FOXO transcription factors * FOX proteins
OECD category: Biochemistry and molecular biology
Impact factor: 7.080, year: 2019
Method of publishing: Open access
https://elifesciences.org/articles/48876

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.
Permanent Link: http://hdl.handle.net/11104/0303731