Highly Specific Inhibition of c-Myc Oncogene Expression through Shifting the G-Quadruplex toward a Triplex Structure.

G-quadruplexes act as transcriptional triggers in oncogenes, and small molecules targeting them show anticancer potential but lack sequence specificity, risking off-target effects. Here, we introduce original fold-back triplex-forming oligonucleotides (FTFOs) as precise alternatives. Physicochemical and biological analyses revealed that FTFOs unfold the c-Myc G-quadruplex and repress oncogene regulatory element by forming noncanonical triplexes that block G-quadruplex DNA from interacting with transcription factors. Derived design rules enabled the identification of FTFOs that reduce c-Myc expression in the Del4 plasmid by up to 80%, significantly impairing cancer cell growth, confluence, mobility, and endogenous c-Myc expression. This work presents FTFOs as an innovative sequence-specific strategy for arresting G-quadruplex structures via triplex formation and suppressing oncogene activity, offering a promising avenue for targeted anticancer therapy.

• Publication year

  2025

• Venue

  Journal of Medicinal Chemistry

• Publication date

  2025-11-12

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1021/acs.jmedchem.5c02386PMID 41223088
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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