Dual Functional Potential of Poly(ADP-Ribose) Polymerase Inhibitor VIII: A Promising G-Quadruplex Stabilizer...

Poly(ADP-ribose) polymerases (PARPs) have emerged as pivotal therapeutic targets due to their essential function in DNA single-strand break repair, particularly in cancers with BRCA1/2 mutations. Although PARP inhibitors show promising clinical responses, their long-term efficacy is often compromised by the development of drug resistance, which limits sustained therapeutic success. To address this, identifying molecules capable of modulating additional cancer-relevant pathways has become an emerging strategy. G-quadruplexes (G4s), enriched in oncogenic promoter regions, have gained considerable attention as therapeutic targets. In this study, we investigated the ability of two PARP inhibitors, PARP inhibitor VIII (PI VIII) and PARP inhibitor XI (PI XI), to bind and stabilize G4 structures using biophysical assays and molecular docking. Our results reveal that PI VIII exhibits a markedly stronger affinity for G4 structures compared to PI XI, with a preference for the G4 motif present in the c-myc oncogene, which is frequently overexpressed in cancer cells. Moreover, PI VIII demonstrates enhanced binding and stabilization of the c-myc G4 relative to duplex DNA. The observed stabilizing effect involves electrostatic interactions, hydrogen bonding, and π-π stacking. These findings identify PI VIII as a promising dual-mode anticancer candidate capable of simultaneously inhibiting PARP activity and stabilizing oncogenic G-quadruplexes.