BYBC-1

BYBC-1 is a highly selective RNA G-quadruplex (G4) targeting ligand with strong affinity for the G4-RNAs of KRAS and NRAS (Kd=0.05-0.28 μM). By stabilizing the G4-RNA structures of KRAS and NRAS, BYBC-1 disrupts the PI3K/AKT and MAPK/ERK pathways, activates the DNA damage response (DDR), inhibits energy metabolism, and induces S phase arrest and apoptosis. It demonstrates high specificity for non-malignant fibroblasts and significantly suppresses the growth of HCT-116 xenografts in vivo. BYBC-1 is applicable for research related to colorectal cancer.

BYBC-1 demonstrates potent anti-cancer cell proliferation activity over 48 hours, with the following IC 50 values: HCT-116 (1.09 μM), SW480 (2.88 μM), PANC-1 (1.38 μM), A549 (2.19 μM), MDA-MB-231 (2.88 μM), SK-MEL-2 (4.74 μM), HepG2 (4.13 μM), and HeLa (3.56 μM), showing more than 20-fold selectivity compared to non-malignant fibroblasts (HFF1 and BJ cells, IC 50 >20 μM). At concentrations of 0.5-2 μM for 48 hours, BYBC-1 downregulates KRAS and NRAS protein expression in HCT-116 cells, inhibits the PI3K/AKT and MAPK/ERK pathways, activates the DNA damage response, impairs HR, BER, NER, and MMR repair pathways, increases CHK1 and CHK2 phosphorylation, and induces S-phase arrest. Additionally, at 0.5-2 μM for 3 hours, BYBC-1 inhibits mitochondrial respiration and glycolysis in HCT-116 cells, while at 0.5-2 μM for 48 hours, it impedes cell migration and apoptosis. Lastly, BYBC-1 prevents the growth of HCT-116 multicellular tumor spheroids over a period of 8 days.

BYBC-1, administered intraperitoneally at doses of 2.5-10.0 mg/kg every other day for 14 days, effectively inhibits tumor growth in HCT-116 xenograft mice and demonstrates good biocompatibility.