Journal
ACS OMEGA
Volume 7, Issue 38, Pages 34632-34646Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsomega.2c04613
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Funding
- Czech Science Foundation [21-02080S]
- Grant Agency of the Charles University [296621]
- Czech Academy of Sciences (Institute of Physiology) [67985823]
- Austrian Science Fund [I3089-B28, FG15]
- Dr. Johannes und Herta Tuba Stiftung
- Charles University Research Centre program [UNCE/SCI/014]
- Austrian Science Fund (FWF)
- Austrian Science Fund (FWF) [FG15] Funding Source: Austrian Science Fund (FWF)
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Increased FOXO3 nuclear localization is involved in neuroblastoma chemoresistance and tumor angiogenesis. Inhibition of FOXO3 is a promising strategy for enhancing antitumor immune responses and suppressing therapy resistance in cancer cells. (4-propoxy)phenylpyrimidinylguanidine has been identified as a FOXO3 inhibitor in cancer cells. The synthesis and structure-activity relationship study of its derivatives showed that some compounds are more potent than the parent compound in inhibiting FOXO3-induced gene transcription. These findings may contribute to the development of therapeutics for inhibiting FOX transcription factors.
Increased FOXO3 nuclear localization is involved in neuroblastoma chemoresistance and tumor angiogenesis. Accord-ingly, 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.
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