Translational Suppression of KRAS and NRAS via RNA G-Quadruplex-Targeting Small Molecules for Colorectal Cancer Therapy.

RAS mutations are major drivers of tumorigenesis and represent important therapeutic targets; however, most remain resistant to effective pharmacological inhibition. KRAS and NRAS mRNAs contain guanine (G)-rich regions, forming stable G-quadruplexes (G4s) that regulate translation. Targeting and stabilizing these G4 structures with specific ligands may suppress their expression, offering a potential therapeutic strategy for RAS-driven cancers. BYBC-1, a novel G4-RNA-targeting ligand, shows strong affinity (Kd = 0.05-0.28 μM) for G4-RNAs, particularly KRAS and NRAS, highlighting its promise as a therapeutic strategy against RAS-driven cancers. BYBC-1 inhibits KRAS and NRAS translation, disrupting PI3K/AKT and MAPK/ERK signaling. It reactivates the DNA damage response, induces S-phase arrest, and suppresses DNA replication and energy metabolism, leading to impaired migration and apoptosis in HCT-116 cells. BYBC-1 showed potent activity against HCT-116 cells (IC50 = 1.09 μM) with >20-fold selectivity over nonmalignant fibroblast cells. In vivo, it reduced tumor weight by 78% in an HCT-116 xenograft mouse model, confirming strong antitumor efficacy.