Glycoconjugated Metallohelices Eliminate Cancer Stem‐Like Cells via Modulating G‐Quadruplex Surrounding Transcriptional Start Site of Sox2 Gene

Abstract As an important pluripotency transcription factor, Sox2 plays key roles in the stemness maintenance of cancer stem‐like cells (CSCs). Here, we found that a highly conserved G‐rich region surrounding transcriptional start sites (TSSs) of Sox2 gene can form G‐quadruplex (Sox2G4) both in vitro and in cells. More intriguingly, the glycoconjugated triplex metallohelice [Fe 2 L Δ‐f 3 ] 4+ (Δ‐f) can enantioselectively stabilize Sox2G4. Sox2G4 stabilization induced by [Fe 2 L Δ‐f 3 ] 4+ (Δ‐f) rather than Λ‐f results in inhibition of Sox2 expression both in mRNA and protein levels in breast CSCs and decreases the cell viability and stemness of breast CSCs. These results indicate that [Fe 2 L Δ‐f 3 ] 4+ (Δ‐f) has the enantioselectivity even in living cells. In vivo studies further demonstrate that Δ‐f can reduce tumor initiation of breast CSCs. To our knowledge, this is the first report that targeting G‐quadruplexes of pluripotency genes can regulate the fates of CSCs. Our work provides a new way to target CSC gene and eradicate cancer stem cells.