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Lengthening the Guanidine–Aryl Linker of Phenylpyrimidinylguanidines Increases Their Potency as Inhibitors of FOXO3-Induced Gene Transcription

SYSNO ASEP	0562268
Document Type	J - Journal Article
R&D Document Type	Journal Article
Subsidiary J	Článek ve WOS
Title	Lengthening the Guanidine–Aryl Linker of Phenylpyrimidinylguanidines Increases Their Potency as Inhibitors of FOXO3-Induced Gene Transcription
Author(s)	Kohoutová, Klára (FGU-C)_ORCID Dočekal, V. (CZ) Ausserlechner, M. J. (AT) Kaiser, N. (AT) Tekel, A. (CZ) Mandal, R. (CZ) Horváth, M. (CZ) Obšilová, Veronika (FGU-C)_{RID, ORCID, SAI} Veselý, J. (CZ) Hagenbuchner, J. (AT) Obšil, Tomáš (FGU-C)_{RID, ORCID}
Source Title	ACS Omega. - : American Chemical Society - ISSN 2470-1343 Roč. 7, č. 38 (2022), s. 34632-34646
Number of pages	15 s.
Language	eng - English
Country	US - United States
Keywords	DNA binding ; forkhead box O 3 ; nuclear magnetic resonance ; neuroblastoma ; chemoresistance ; senescence
OECD category	Biochemistry and molecular biology
R&D Projects	GA21-02080S GA ČR - Czech Science Foundation (CSF)
Method of publishing	Open access
Institutional support	FGU-C - RVO:67985823
UT WOS	000862940400001
EID SCOPUS	85139331926
DOI	10.1021/acsomega.2c04613
Annotation	Increased FOXO3 nuclear localization is involved in neuroblastoma chemoresistance and tumor angiogenesis. Accordingly, FOXO3 inhibition is a promising strategy for boosting antitumor immune responses and suppressing FOXO3-mediated therapy resistance in cancer cells. However, no FOXO3 inhibitors are currently available for clinical use. Nevertheless, we have recently identified (4-propoxy)phenylpyrimidinylguanidine as a FOXO3 inhibitor in cancer cells in the low micromolar range. Here, we report the synthesis and structure–activity relationship study of a small library of its derivatives, some of which inhibit FOXO3-induced gene transcription in cancer cells in a submicromolar range and are thus 1 order of magnitude more potent than their parent compound. By NMR and molecular docking, we showed that these compounds differ in their interactions with the DNA-binding domain of FOXO3. These results may provide a foundation for further optimizing (4-propoxy)phenylpyrimidinylguanidine and developing therapeutics for inhibiting the activity of forkhead box (FOX) transcription factors and their interactions with other binding partners.
Workplace	Institute of Physiology
Contact	Lucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400
Year of Publishing	2023
Electronic address	https://doi.org/10.1021/acsomega.2c04613

Number of the records: 1