Discovery of Voreloxin as a Dual-Selective Stabilizer for c-Myc/Bcl-2 G-Quadruplexes in Leukemia

Overexpression of c-Myc is a key factor in the development of leukemia and other malignancies, highlighting the urgent need for novel drugs to inhibit c-Myc protein levels. DNA G-quadruplexes (G4) have emerged as potential regulatory targets for c-Myc expression. Previous studies identified trovafloxacin, a topoisomerase II inhibitor, as a novel c-Myc G4 stabilizer. In this study, virtual screening based on structural similarity led to the identification of nine derivatives of trovafloxacin, among which voreloxin exhibited potent cytotoxicity in multiple myeloma cells and showed promising therapeutic efficacy in leukemia cells. FRET assays demonstrated that voreloxin specifically stabilized the G4 structures of c-Myc and Bcl-2, with minimal effects on the G4 structures of other oncogenes. Moreover, voreloxin significantly reduced the expression levels of c-Myc and Bcl-2 in THP-1 and MOLM-13 cells. Molecular docking, molecular dynamics (MD) simulations, and MM/GBSA calculations further confirmed the stable binding of voreloxin to both c-Myc and Bcl-2 G4s, primarily driven by pi-pi stacking and hydrogen bonding interactions. These findings provide valuable insights for the development of G4-targeting drugs for cancer therapy.