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

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.

Automated summary

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.