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

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• RAS mutations are key drivers of cancer, but effective therapies remain limited.
• Guanine-rich regions in KRAS and NRAS mRNAs form G-quadruplexes (G4s) that regulate translation.
• Targeting G4 structures presents a potential therapeutic strategy for RAS-driven cancers.

Purpose of the Study:

• To evaluate BYBC-1, a novel G4-RNA-targeting ligand, as a therapeutic agent against RAS-driven cancers.
• To investigate the molecular mechanisms underlying BYBC-1's antitumor activity.
• To assess BYBC-1's efficacy and selectivity in cellular and in vivo models.

Main Methods:

• Characterization of BYBC-1's binding affinity to G4-RNAs, including KRAS and NRAS.
• Assessment of BYBC-1's effects on KRAS and NRAS translation and downstream signaling pathways (PI3K/AKT, MAPK/ERK).
• Evaluation of BYBC-1's impact on DNA damage response, cell cycle progression, and cellular functions (migration, apoptosis) in HCT-116 cells.
• In vivo efficacy studies using an HCT-116 xenograft mouse model.

Main Results:

• BYBC-1 demonstrated strong affinity for G4-RNAs, particularly KRAS and NRAS (Kd = 0.05-0.28 μM).
• BYBC-1 inhibited KRAS and NRAS translation, disrupted PI3K/AKT and MAPK/ERK signaling, induced S-phase arrest, and promoted apoptosis in HCT-116 cells.
• BYBC-1 exhibited potent activity against HCT-116 cells (IC50 = 1.09 μM) with significant selectivity over normal cells.
• In vivo, BYBC-1 reduced tumor weight by 78% in an HCT-116 xenograft model.

Conclusions:

• BYBC-1 is a promising G4-RNA-targeting ligand with potent antitumor activity against RAS-driven cancers.
• BYBC-1's mechanism involves inhibition of KRAS/NRAS translation and disruption of key oncogenic signaling pathways.
• BYBC-1 demonstrates favorable efficacy and selectivity, warranting further investigation as a therapeutic candidate.