biostudies-literatureAlexandrou EBiotechnology and Biological Sciences Research Council55-58https://www.ebi.ac.uk/biostudies/studies/S-EPMC10732280biostudies-literatureUnknown22(1)GC-rich sequences can fold into G-quadruplexes and i-motifs and are known to control gene expression in many organisms. The potent G-quadruplex experimental anticancer drug QN-302 down-regulates a number of cancer-related genes, in particular <i>S100P</i>. Here we show this ligand has strong opposing effects with i-motif DNA structures and is one of the most potent i-motif destabilising agents reported to date. QN-302 down-regulates the expression of numerous cancer-related genes by pan-quadruplex targeting. QN-302 exhibits exceptional combined synergistic effects compared to many other G-quadruplex and i-motif interacting compounds. This work further emphasises the importance of considering G-quadruplex and i-motif DNA structures as one dynamic system.Organic & biomolecular chemistryQN-302 demonstrates opposing effects between i-motif and G-quadruplex DNA structures in the promoter of the S100P gene.PMC10732280BB/W001616/1Alexandrou EGuneri DWaller ZAENeidle SfalseQN-302 demonstrates opposing effects between i-motif and G-quadruplex DNA structures in the promoter of the S100P gene.GC-rich sequences can fold into G-quadruplexes and i-motifs and are known to control gene expression in many organisms. The potent G-quadruplex experimental anticancer drug QN-302 down-regulates a number of cancer-related genes, in particular <i>S100P</i>. Here we show this ligand has strong opposing effects with i-motif DNA structures and is one of the most potent i-motif destabilising agents reported to date. QN-302 down-regulates the expression of numerous cancer-related genes by pan-quadruplex targeting. QN-302 exhibits exceptional combined synergistic effects compared to many other G-quadruplex and i-motif interacting compounds. This work further emphasises the importance of considering G-quadruplex and i-motif DNA structures as one dynamic system.2023-01-01T00:00:00Z2023 Dec2025-04-29T09:56:01.862Z2025-04-06T19:20:23.171ZS-EPMC107322803797088810.1039/d3ob01464a