G-quadruplex (G4)

G-quadruplexes (G4s) are non-canonical secondary structures formed in guanine-rich sequences of DNA and RNA through Hoogsteen base pairing, which facilitates the assembly of stacked planar G-tetrads stabilized by monovalent cations [1][2]. These structures are highly prevalent in critical genomic regions, including telomeres and the promoter regions of oncogenes such as c-MYC, KRAS, and BCL2, where they act as molecular switches for transcription and replication [2][3]. In oncology, G-quadruplexes are targeted by small-molecule stabilizers to suppress the expression of drivers of malignancy or to disrupt telomere capping, leading to selective senescence or apoptosis in cancer cells [3][4]. Beyond cancer, G4 structures are involved in the regulation of viral genomes (e.g., HIV-1, SARS-CoV-2) and the pathogenesis of neurodegenerative diseases, where hexanucleotide repeats can form toxic G4 aggregates [5][6]. Therapeutic candidates like CX-5461 (Pidnarulex) have demonstrated the potential to exploit G4-mediated synthetic lethality, particularly in tumors with DNA repair deficiencies [4][7]. However, the widespread occurrence of G4 motifs throughout the human genome poses significant challenges for drug selectivity and the prevention of systemic toxicity [1][8]. [1] Rhodes D, Lipps HJ. G-quadruplexes. Nucleic Acids Res. 2015. [2] Spiegel J, et al. G-quadruplexes: online at last. Trends Chem. 2020. [3] Balasubramanian S, Neidle S. G-quadruplexes as therapeutic targets. Curr Opin Chem Biol. 2009. [4] Xu H, et al. CX-5461 is a G-quadruplex stabilizer that selectively induces DNA damage. Nat Commun. 2017. [5] Frasson I, et al. G-quadruplexes as targets for antiviral therapy. Med Res Rev. 2022. [6] Simone R, et al. G-quadruplexes: emerging roles in neurodegenerative diseases. FEBS Lett. 2015. [7] Drygin D, et al. Targeting RNA polymerase I with an oral small molecule CX-5461. Cancer Res. 2011. [8] Neidle S. Quadruplex nucleic acids as targets for anticancer therapeutics. Nat Rev Drug Discov. 2009.

Other names

G4 DNAG4 RNAG-tetraplexGuanine-quadruplexG-rich secondary structure

Small-molecule ligands bind and stabilize G-quadruplex structures to inhibit telomerase activity, repress the transcription of oncogenes (such as c-MYC or KRAS), interfere with viral replication, or induce site-specific DNA damage and apoptosis in cancer cells.