Down-Regulation of Oncogene c-myb Specifically by Carbazole Derivative Through Opposing Effects on Different...

Cancer is one of the leading causes of human mortality worldwide, and aberrant expression of the c-myb oncogene is closely associated with the development of numerous malignancies. The c-myb promoter region contains G-rich and C-rich sequences capable of forming G-quadruplex (G4) and i-motif (IM or C-quadruplex) structures, respectively. These secondary structures function as "molecular switches" for gene transcriptional regulation and represent promising targets for novel anti-tumor therapeutics. Through extensive screening, we identified carbazole derivative G51 as a unique dual-targeting ligand that simultaneously destabilized the i-motif and stabilized the G-quadruplex, consequently suppressing c-myb expression efficiently. In comparison, the single-targeting ligand G50, which could specifically bind to and unfold the G-quadruplex only, exhibited significantly weaker anti-tumor activity than G51. Notably, G51 showed potent anti-tumor efficacy in a human colorectal cancer xenograft model without significant toxicity to vital organs. G51, as a dual-targeting ligand, had specific binding to c-myb promoter quadruplexes, with destabilization of the i-motif and concurrent stabilization of the G-quadruplex. This opposing effect could provide a good opportunity for specific gene regulation, with great potential for further development of a precise therapeutic agent. This study provides a novel example for a practical therapeutic approach through coordinated gene quadruplex modulations, which sets up a good foundation for developing high-efficacy anti-tumor drugs without significant side effects.