Discovery of Clinically Used Octenidine as Repressor That Effectively Inhibits -Mutant Melanoma.

Mutations in promote tumorigenesis and drug resistance. As this protein is often considered an undruggable target, it is urgent to develop novel strategies to suppress for anticancer therapy. Recent reports indicated that a G-quadruplex (G4) structure formed in the untranslated region of mRNA can downregulate translation, suggesting a potential suppression strategy. Here, we developed a novel cell-based method for large-scale screening of G4 ligand using the G-quadruplex-triggered fluorogenic hybridization probe and successfully identified the clinically used agent Octenidine as a potent repressor. This compound suppressed translation, blocked the MAPK and PI3K-AKT signaling, and caused concomitant cell cycle arrest, apoptosis, and autophagy. It exhibited better antiproliferation effects over clinical antimelanoma agents and could inhibit the growth of -mutant melanoma in a xenograft mouse model. Our results suggest that Octenidine may be a prominent anti--mutant melanoma agent and represent a new -mutant melanoma therapy option.