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Quadruplex nucleic acids as targets for anticancer therapeutics

Nature Reviews Chemistry volume 1, Article number: 0041 (2017) Cite this article

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Abstract

Quadruplex nucleic acids — helical four-stranded structures known to form from guanine-rich nucleic acid sequences through Hoogsteen-type hydrogen bonding — were once just laboratory curiosities. However, they are now emerging from this rather obscure status to become important targets for small-molecule drugs, which can stabilize the quadruplex structures and thereby promote selective downregulation of gene expression and telomerase inhibition, and also activate DNA damage responses. Most of these quadruplex-binding small molecules can stabilize a range of cellular quadruplexes, as well as clusters of quadruplexes within a single gene or telomere, which could be an advantage. This widespread stabilization can generate a polygene response, and thus is able to simultaneously affect several key driver genes in human cancers, with potential therapeutic benefit.

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Figure 1: The G—quartet.
Figure 2: Cartoon representation of three distinct topologies observed for intramolecular telomeric G4s.
Figure 3: Chemical structures of selected G4—binding ligands.
Figure 4: Structures of selected G4-binding compounds.

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References

  1. Hargrove, A. E. et al. Tumor repression of VCaP xenografts by a pyrrole–imidazole polyamide. PLoS ONE 10, e0143161 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Flynn, M. J. et al. ADCT-301, a pyrrolobenzodiazepine (PBD) dimer-containing antibody–drug conjugate (ADC) targeting CD25-expressing hematological malignancies. Mol. Cancer Ther. 15, 2709–2721 (2016).

    Article  CAS  PubMed  Google Scholar 

  3. Gellert, M., Lipsett, M. N. & Davies, D. R. Helix formation by guanylic acid. Proc. Natl Acad. Sci. USA 48, 2013–2018 (1962).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bhattacharyya, D., Mirihana Arachchilage, G. & Basu, S. Metal cations in G-quadruplex folding and stability. Front. Chem. 4, 38 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Henderson, E., Hardin, C. C., Walk, S. K., Tinoco, I. Jr & Blackburn, E. H. Telomeric DNA oligonucleotides form novel intramolecular structures containing guanine–guanine base pairs. Cell 51, 899–908 (1987).

    Article  CAS  PubMed  Google Scholar 

  6. Sen, D. & Gilbert, W. Formation of parallel four-stranded complexes by guanine-rich motifs in DNA and its implications for meiosis. Nature 334, 364–366 (1988).

    Article  CAS  PubMed  Google Scholar 

  7. Sundquist, W. I. & Klug, A. Telomeric DNA dimerizes by formation of guanine tetrads between hairpin loops. Nature 342, 825–829 (1989).

    Article  CAS  PubMed  Google Scholar 

  8. Simonsson, T., Pecinka, P. & Kubista, M. DNA tetraplex formation in the control region of c-myc. Nucleic Acids Res. 26, 1167–1172 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Laughlan, G. et al. The high-resolution crystal structure of a parallel-stranded guanine tetraplex. Science 265, 520–524 (1994).

    Article  CAS  PubMed  Google Scholar 

  10. Wang, Y. & Patel, D. J. Solution structure of the human telomeric repeat d[AG3(T2AG3)3] G-tetraplex. Structure 1, 263–282 (1993).

    Article  CAS  PubMed  Google Scholar 

  11. Burge, S., Parkinson, G. N., Hazel, P., Todd, A. K. & Neidle, S. Quadruplex DNA: sequence, topology and structure. Nucleic Acids Res. 34, 5402–5415 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Adrian, M., Heddi, B. & Phan, A. T. NMR spectroscopy of G-quadruplexes. Methods 57, 11–24 (2012).

    Article  CAS  PubMed  Google Scholar 

  13. Parkinson, G. N., Lee, M. P. & Neidle, S. Crystal structure of parallel quadruplexes from human telomeric DNA. Nature 417, 876–880 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Luu, K. N. et al. Structure of the human telomere in K+ solution: an intramolecular (3 + 1) G-quadruplex scaffold. J. Am. Chem. Soc. 128, 9963–9970 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Brcˇic´, J. & Plavec, J. Solution structure of a DNA quadruplex containing ALS and FTD related GGGGCC repeat stabilized by 8-bromodeoxyguanosine substitution. Nucleic Acids Res. 43, 8590–8600 (2015).

    Article  CAS  Google Scholar 

  16. Vasilyev, N. et al. Crystal structure reveals specific recognition of a G-quadruplex RNA by a β-turn in the RGG motif of FMRP. Proc. Natl Acad. Sci. USA 112, 5391–5400 (2015).

    Article  CAS  Google Scholar 

  17. De Nicola, B. et al. Structure and possible function of a G-quadruplex in the long terminal repeat of the proviral HIV-1 genome. Nucleic Acids Res. 44, 6442–6451 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Dai, J., Carver, M., Punchihewa, C., Jones, R. A. & Yang, D. Structure of the hybrid-2 type intramolecular human telomeric G-quadruplex in K+ solution: insights into structure polymorphism of the human telomeric sequence. Nucleic Acids Res. 35, 4927–4740 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lim, K. W. et al. Structure of the human telomere in K+ solution: a stable basket-type G-quadruplex with only two G-tetrad layers. J. Am. Chem. Soc. 131, 4301–4309 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Heddi, B. & Phan, A. T. Structure of human telomeric DNA in crowded solution. J. Am. Chem. Soc. 133, 9824–9833 (2013).

    Article  CAS  Google Scholar 

  21. Monchaud, D. & Teulade-Fichou, M.-P. A hitchhiker's guide to G-quadruplex ligands. Org. Biomol. Chem. 6, 627–636 (2008).

    Article  CAS  PubMed  Google Scholar 

  22. Müller, S. & Rodriguez, R. G-Quadruplex interacting small molecules and drugs: from bench towards bedside. Expert. Rev. Clin. Pharmacol. 7, 663–679 (2014).

    Article  PubMed  CAS  Google Scholar 

  23. Islam, M. K., Jackson, P. J., Rahman, K. M. & Thurston, D. E. Recent advances in targeting the telomeric G-quadruplex DNA sequence with small molecules as a strategy for anticancer therapies. Future Med. Chem. 8, 1259–1290 (2016).

    Article  CAS  PubMed  Google Scholar 

  24. Kejnovská, I., Vorlícˇková, M., Brázdová, M. & Sagi, J. Stability of human telomere quadruplexes at high DNA concentrations. Biopolymers 101, 428–438 (2014).

    Article  PubMed  CAS  Google Scholar 

  25. Liu, H. Y. et al. Conformation selective antibody enables genome profiling and leads to discovery of parallel G-quadruplex in human telomeres. Cell Chem. Biol. 23, 1261–1270 (2016).

    Article  CAS  PubMed  Google Scholar 

  26. Moye, A. L. et al. Telomeric G-quadruplexes are a substrate and site of localization for human telomerase. Nat. Commun. 6, 7643 (2015).

    Article  PubMed  Google Scholar 

  27. Wright, W. E., Tesmer, V. M., Huffman, K. E., Levene, S. D. & Shay, J. W. Normal human chromosomes have long G-rich telomeric overhangs at one end. Genes Dev. 11, 2801–2809 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zaug, A. J. Podell, E. R. & Cech, T. R. Human POT1 disrupts telomeric G-quadruplexes allowing telomerase extension in vitro .. Proc. Natl Acad. Sci. USA 102, 10864–10869 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yu, H. Q., Miyoshi, D. & Sugimoto, N. Characterization of structure and stability of long telomeric DNA G-quadruplexes. J. Am. Chem. Soc. 128, 15461–15468 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Bugaut, A. & Alberti, P. Understanding the stability of DNA G-quadruplex units in long human telomeric strands. Biochimie 113, 125–133 (2015).

    Article  CAS  PubMed  Google Scholar 

  31. Haider, S. M. & Neidle, S. A molecular model for drug binding to tandem repeats of telomeric G-quadruplexes. Biochem. Soc. Trans. 37, 583–588 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Petraccone, L. et al. Structure and stability of higher-order human telomeric quadruplexes. J. Am. Chem. Soc. 133, 20951–20961 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sun, D. et al. Inhibition of human telomerase by a G-quadruplex-interactive compound. J. Med. Chem. 40, 2113–2116 (1997).

    Article  CAS  PubMed  Google Scholar 

  34. Campbell, N. H., Parkinson, G. N., Reszka, A. P. & Neidle, S. Structural basis of DNA quadruplex recognition by an acridine drug. J. Am. Chem. Soc. 130, 6722–6724 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Burger, A. M. et al. The G-quadruplex-interactive molecule BRACO-19 inhibits tumor growth, consistent with telomere targeting and interference with telomerase function. Cancer Res. 65, 1489–1496 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Zhou, G. et al. Telomere targeting with a novel G-quadruplex-interactive ligand BRACO-19 induces T-loop disassembly and telomerase displacement in human glioblastoma cells. Oncotarget 7, 14925–14939 (2016).

    PubMed  PubMed Central  Google Scholar 

  37. Brown, J. S., O'Carrigan, B., Jackson, S. P. & Yap, T. A. Targeting DNA repair in cancer: beyond PARP inhibitors. Cancer Discov. 7, 20–37 (2017).

    Article  CAS  PubMed  Google Scholar 

  38. Cookson, J. C. et al. Pharmacodynamics of the G-quadruplex-stabilizing telomerase inhibitor 3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl] acridinium methosulfate (RHPS4) in vitro: activity in human tumor cells correlates with telomere length and can be enhanced, or antagonized, with cytotoxic agents. Mol. Pharmacol. 68, 1551–1558 (2005).

    CAS  PubMed  Google Scholar 

  39. Salvati, E. et al. Telomere damage induced by the G-quadruplex ligand RHPS4 has an antitumor effect. J. Clin. Invest. 117, 3236–3247 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Salvati, E. et al. PARP1 is activated at telomeres upon G4 stabilization: possible target for telomere-based therapy. Oncogene 29, 6280–6293 (2010).

    Article  CAS  PubMed  Google Scholar 

  41. Rodriguez, R. et al. A novel small molecule that alters shelterin integrity and triggers a DNA-damage response at telomeres. J. Am. Chem. Soc. 130, 15758–15759 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Rodriguez, R. et al. Small-molecule-induced DNA damage identifies alternative DNA structures in human genes. Nat. Chem. Biol. 8, 301–310 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Müller, S. et al. Pyridostatin analogues promote telomere dysfunction and long-term growth inhibition in human cancer cells. Org. Biomol. Chem. 10, 6537–6546 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Iachettini, S. et al. On and off-target effects of telomere uncapping G-quadruplex selective ligands based on pentacyclic acridinium salts. J. Exp. Clin. Cancer Res. 32, 68 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Rizzo, A. et al. Identification of novel RHPS4-derivative ligands with improved toxicological profiles and telomere-targeting activities. J. Exp. Clin. Cancer Res. 33, 81 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Chung, W. J. et al. Solution structure of an intramolecular (3 + 1) human telomeric G-quadruplex bound to a telomestatin derivative. J. Am. Chem. Soc. 135, 13495–13501 (2013).

    Article  CAS  PubMed  Google Scholar 

  47. Siddiqui-Jain, A., Grand, C. L., Bearss, D. J. & Hurley, L. H. Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-MYC transcription. Proc. Natl Acad. Sci. USA 99, 11593–11598 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Balasubramanian, S., Hurley, L. H. & Neidle, S. Targeting G-quadruplexes in gene promoters: a novel anticancer strategy? Nat. Rev. Drug Discov. 10, 261–275 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Rigo, R., Palumbo, M. & Sissi, C. G-Quadruplexes in human promoters: a challenge for therapeutic applications. Biochim. Biophys. Acta 4165, 30518–30519 (2016).

    Google Scholar 

  50. Todd, A. K., Johnston, M. & Neidle, S. Highly prevalent putative quadruplex sequence motifs in human DNA. Nucleic Acids Res. 33, 2901–2907 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Huppert, J. L. & Balasubramanian, S. Prevalence of quadruplexes in the human genome. Nucleic Acids Res. 33, 2908–2916 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Bedrat, A., Lacroix, L. & Mergny, J.-L. Re-evaluation of G-quadruplex propensity with G4Hunter. Nucleic Acids Res. 44, 1746–1759 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Chambers, V. S. et al. High-throughput sequencing of DNA G-quadruplex structures in the human genome. Nat. Biotechnol. 33, 877–881 (2015).

    Article  PubMed  Google Scholar 

  54. Huppert, J. L. & Balasubramanian, S. G-Quadruplexes in promoters throughout the human genome. Nucleic Acids Res. 35, 406–413 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. Bugaut, A. & Balasubramanian, S. 5′-UTR RNA G-quadruplexes: translation regulation and targeting. Nucleic Acids Res. 40, 4727–4741 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Maizels, N. & Gray, L. T. The G4 genome. PLoS Genet. 9, e1003468 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Murat, P. & Balasubramanian, S. Existence and consequences of G-quadruplex structures in DNA. Curr. Opin. Genet. Dev. 25, 22–29 (2014).

    Article  CAS  PubMed  Google Scholar 

  58. Rhodes, D. & Lipps, H. J. G-Quadruplexes and their regulatory roles in cancer. Nucleic Acids Res. 43, 8627–8637 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Bochman, M. L., Paeschke, K. & Zakian, V. A. DNA secondary structures: stability and function of G-quadruplex structures. Nat. Rev. Genet. 13, 770–780 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Hänsel-Hertsch, R. et al. G-Quadruplex structures mark human regulatory chromatin. Nat. Genet. 48, 1267–1272 (2016).

    Article  PubMed  CAS  Google Scholar 

  61. Guo, J. U. & Bartel, D. P. RNA G-quadruplexes are globally unfolded in eukaryotic cells and depleted in bacteria. Science http://dx.doi.org/10.1126/science.aaf5371 (2016).

  62. Dai, J., Carver, M., Hurley, L. H. & Yang, D. Solution structure of a 2:1 quindoline–c-MYC G-quadruplex: insights into G-quadruplex interactive small molecule drug design. J. Am. Chem. Soc. 133, 17673–17680 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Schaffitzel, C. et al. In vitro generated antibodies specific for telomeric guanine-quadruplex DNA react with Stylonychia lemnae macronuclei. Proc. Natl Acad. Sci. USA 98, 8572–8577 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Lam, E. Y. N., Beraldi, D., Tannahill, D. & Balasubramanian, S. G-Quadruplex structures are stable and detectable in human genomic DNA. Nat. Commun. 4, 1796–1780 (2013).

    Article  PubMed  CAS  Google Scholar 

  65. Biffi, G., Tannahill, D., McCafferty, J. & Balasubramanian, S. Quantitative visualization of DNA G-quadruplex structures in human cells. Nat. Chem. 5, 182–186 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Henderson, A. et al. Detection of G-quadruplex DNA in mammalian cells. Nucleic Acids Res. 42, 860–869 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Biffi, G., Di Antonio, M., Tannahill, D. & Balasubramanian, S. Visualization and selective chemical targeting of RNA G-quadruplex structures in the cytoplasm of human cells. Nat. Chem. 6, 75–80 (2014).

    Article  CAS  PubMed  Google Scholar 

  68. Biffi, G., Tannahill, D., Miller, J., Howat, W. J. & Balasubramanian, S. Elevated levels of G-quadruplex formation in human stomach and liver cancer tissues. PLoS ONE 9, e102711 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Mendoza, O., Bourdoncle, A., Boulé, J.-B., Brosh, R. M. Jr & Mergny, J.-L. G-Quadruplexes and helicases. Nucleic Acids Res. 44, 1989–2006 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Tseng, T.-Y. et al. Fluorescent probe for visualizing guanine-quadruplex DNA by fluorescence lifetime imaging microscopy. J. Biomed. Opt. 18, 101309 (2013).

    Article  PubMed  CAS  Google Scholar 

  71. Laguerre, A. et al. Visualization of RNA-quadruplexes in live cells. J. Am. Chem. Soc. 137, 8521–8525 (2015).

    Article  CAS  PubMed  Google Scholar 

  72. Shivalingam, A. et al. The interactions between a small molecule and G-quadruplexes are visualized by fluorescence lifetime imaging microscopy. Nat. Commun. 6, 8178 (2015).

    Article  CAS  PubMed  Google Scholar 

  73. Doria, F. et al. A red-NIR fluorescent dye detecting nuclear DNA G-quadruplexes: in vitro analysis and cell imaging. Chem. Commun. 53, 2268–2271 (2017).

    Article  CAS  Google Scholar 

  74. Cogoi, S. & Xodo, L. E. G4 DNA in ras genes and its potential in cancer therapy. Biochim. Biophys. Acta 1859, 663–674 (2016).

    Article  CAS  PubMed  Google Scholar 

  75. Paulo, A. & Francisco, A. P. Oncogene expression modulation in cancer cell lines by DNA G-quadruplex-interactive small molecules. Curr. Med. Chem. http://dx.doi.org/10.2174/0929867323666160829145055 (2016).

  76. Phan, A. T., Kuryavyi, V., Burge, S., Neidle, S. & Patel, D. J. Structure of an unprecedented G-quadruplex scaffold in the human c-kit promoter. J. Am. Chem. Soc. 129, 4386–4392 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Hsu, S. T. et al. G-Rich sequence within the c-kit oncogene promoter forms a parallel G-quadruplex having asymmetric G-tetrad dynamics. J. Am. Chem. Soc. 131, 13399–13409 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Kuryavyi, V., Phan, A. T. & Patel, D. J. Solution structures of all parallel-stranded monomeric and dimeric G-quadruplex scaffolds of the human c-kit2 promoter. Nucleic Acids Res. 38, 6757–6773 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Dai, J., Chen, D., Jones, R. A., Hurley, L. H. & Yang, D. NMR solution structure of the major G-quadruplex structure formed in the human BCL2 promoter region. Nucleic Acids Res. 34, 5133–5144 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Agrawal, P., Lin, C., Mathad, R. I., Carver, M. & Yang, D. The major G-quadruplex formed in the human BCL-2 proximal promoter adopts a parallel structure with a 13-nt loop in K+ solution. J. Am. Chem. Soc. 136, 1750–1753 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Agrawal, P., Hatzakis, E., Guo, K., Carver, M. & Yang, D. Solution structure of the major G-quadruplex formed in the human VEGF promoter in K+: insights into loop interactions of the parallel G-quadruplexes. Nucleic Acids Res. 41, 10584–10592 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Kerkour, A. et al. High-resolution 3D NMR structure of the KRAS proto-oncogene promoter reveals key features of a G-quadruplex involved in transcriptional regulation. J. Biol. Chem. http://dx.doi.org/10.1074/jbc.M117.781906 (2017).

  83. Wei, D., Parkinson, G. N., Reszka, A. P. & Neidle, S. Crystal structure of a c-kit promoter quadruplex reveals the structural role of metal ions and water molecules in maintaining loop conformation. Nucleic Acids Res. 40, 4691–4700 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Wei, D., Husby, J. & Neidle, S. Flexibility and structural conservation in a c-KIT G-quadruplex. Nucleic Acids Res. 43, 629–644 (2015).

    Article  CAS  PubMed  Google Scholar 

  85. Martino, L., Pagano, B., Fotticchia, I., Neidle, S. & Giancola, C. Shedding light on the interaction between TMPyP4 and human telomeric quadruplexes. J. Phys. Chem. B. 113, 14779–14786 (2009).

    Article  CAS  PubMed  Google Scholar 

  86. Guédin, A., Lacroix, L. & Mergny, J.-L. Thermal melting studies of ligand DNA interactions. Methods Mol. Biol. 613, 25–35 (2010).

    Article  PubMed  CAS  Google Scholar 

  87. Jana, J. et al. Chelerythrine down regulates expression of VEGFA, BCL2 and KRAS by arresting G-quadruplex structures at their promoter regions. Sci. Rep. 7, 40706 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Boddupally, P. V. et al. Anticancer activity and cellular repression of c-MYC by the G-quadruplex-stabilizing 11-piperazinylquindoline is not dependent on direct targeting of the G-quadruplex in the c-MYC promoter. J. Med. Chem. 55, 6076–6086 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Brown, R. V., Danford, F. L., Gokhale, V., Hurley, L. H. & Brooks, T. A. Demonstration that drug-targeted down-regulation of MYC in non-Hodgkins lymphoma is directly mediated through the promoter G-quadruplex. J. Biol. Chem. 286, 41018–41027 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Franceschin, M. et al. Aromatic core extension in the series of N-cyclic bay-substituted perylene G-quadruplex ligands: increased telomere damage, antitumor activity, and strong selectivity for neoplastic over healthy cells. ChemMedChem 7, 2144–2154 (2012).

    Article  CAS  PubMed  Google Scholar 

  91. Porru, M. et al. Targeting G-quadruplex DNA structures by EMICORON has a strong antitumor efficacy against advanced models of human colon cancer. Mol. Cancer Ther. 14, 2541–2551 (2015).

    Article  CAS  PubMed  Google Scholar 

  92. Micheli, E. et al. Perylene and coronene derivatives binding to G-rich promoter oncogene sequences efficiently reduce their expression in cancer cells. Biochimie 125, 223–231 (2016).

    Article  CAS  PubMed  Google Scholar 

  93. Zimmer, J. et al. Targeting BRCA1 and BRCA2 deficiencies with G-quadruplex-interacting compounds. Mol. Cell 61, 449–460 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Micco, M. et al. Structure-based design and evaluation of naphthalene diimide G-quadruplex ligands as telomere targeting agents in pancreatic cancer cells. J. Med. Chem. 56, 2959–2974 (2013).

    Article  CAS  PubMed  Google Scholar 

  95. Nadai, M. et al. Assessment of gene promoter G-quadruplex binding and modulation by a naphthalene diimide derivative in tumor cells. Int. J. Oncol. 46, 369–380 (2015).

    Article  CAS  PubMed  Google Scholar 

  96. Ohnmacht, S. A. et al. A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer. Sci. Rep. 5, 11385 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Alizadeh, A. A. et al. Toward understanding and exploiting tumor heterogeneity. Nat. Med. 21, 846–853 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Jamal-Hanjani, M., Quezada, S. A., Larkin, J. & Swanton, C. Translational implications of tumor heterogeneity. Clin. Cancer Res. 21, 1258–1266 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Hänsel-Hertsch, R., Di Antonio, M. & Balasubramanian, S. DNA G-quadruplexes in the human genome: detection, functions and therapeutic potential. Nat. Rev. Mol. Cell Biol. http://dx.doi.org/10.1038/nrm.2017.3 (2017).

  100. Drygin, D. et al. Anticancer activity of CX-3543: a direct inhibitor of rRNA biogenesis. Cancer Res. 69, 7653–7661 (2009).

    Article  CAS  PubMed  Google Scholar 

  101. Xu, H. et al. CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours. Nat. Commun. 8, 14432 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Workman, P., Draetta, G. F., Schellens, J. H. & Bernards, R. How much longer will we put up with $100,000 cancer drugs? Cell 168, 579–583 (2017).

    Article  CAS  PubMed  Google Scholar 

  103. Yu, H., Gu, X., Nakano, S. I., Miyoshi, D. & Sugimoto, N. Beads-on-a-string structure of long telomeric DNAs under molecular crowding conditions. J. Am. Chem. Soc. 134, 20060–20069 (2012).

    Article  CAS  PubMed  Google Scholar 

  104. Cousins, A. R. et al. Ligand selectivity in stabilising tandem parallel folded G-quadruplex motifs in human telomeric DNA sequences. Chem. Commun. 50, 15202–15205 (2014).

    Article  CAS  Google Scholar 

  105. Vilar, R. et al. Dinickel–salphen complexes as binders of human telomeric dimeric G-quadruplexes. Chem. Eur. J. http://dx.doi.org/10.1002/chem.201700276 (2017).

  106. Reed, J. E., Arnal, A. A., Neidle, S. & Vilar, R. Stabilization of G-quadruplex DNA and inhibition of telomerase activity by square-planar nickel(II) complexes. J. Am. Chem. Soc. 128, 5992–5993 (2006).

    Article  CAS  PubMed  Google Scholar 

  107. Funke, A., Dickerhoff, J. & Weisz, K. Towards the development of structure-selective G-quadruplex-binding indolo[3,2-b]quinolines. Chem. Eur. J. 22, 3170–3181 (2016).

    Article  CAS  PubMed  Google Scholar 

  108. Felsenstein, K. M. et al. Small molecule microarrays enable the identification of a selective, quadruplex-binding inhibitor of MYC expression. ACS Chem. Biol. 11, 139–148 (2016).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The author acknowledges support from the Pancreatic Cancer Research Fund, the Medical Research Council (UK), the Wellcome Trust, Johnson & Johnson and the University College London Technology Fund, and thanks a number of colleagues for useful discussions, especially R. Angell, S. Haider, R. Vilar and S. Balasubramanian.

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Authors and Affiliations

  1. Stephen Neidle is at the UCL School of Pharmacy, University College London, London, WC1N 1AX, UK

    Stephen Neidle

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  1. Stephen Neidle
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Correspondence to Stephen Neidle.

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Neidle, S. Quadruplex nucleic acids as targets for anticancer therapeutics. Nat Rev Chem 1, 0041 (2017). https://doi.org/10.1038/s41570-017-0041

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