The Red box as selective G-quadruplex binder that downregulates c-MYC expression in human cells

G-quadruplex (G4) structures within oncogene promoters represent promising therapeutic targets, particularly in the context of transcriptional regulation. Here, we report that the Red box, a fully organic macrocyclic cationic receptor, exhibits high-affinity and selectivity for G4 structures. Biophysical analyses reveal that the Red box binds the c-MYC G4 with nanomolar affinity, stronger than most reported c-MYC ligands. Notably, the Red box displays greater selectivity for c-MYC over duplex DNA compared to the well-characterized porphyrin TMPyP4 and its macrocyclic architecture is essential for this activity, as its acyclic analogue displays negligible G4 stabilization. In cellular assays, treatment with non-cytotoxic concentrations of the Red box selectively downregulated c-MYC expression in HEK293T cells, with minimal effects on c-KIT and hTERT. Furthermore, c-MYC suppression was proportional to its basal expression across several cell lines, supporting a G4-mediated mechanism.