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. 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.