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Targeting G-quadruplexes in gene promoters: a novel anticancer strategy?

Nature Reviews Drug Discovery volume 10, pages 261–275 (2011)Cite this article

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Abstract

G-quadruplexes are four-stranded DNA structures that are over-represented in gene promoter regions and are viewed as emerging therapeutic targets in oncology, as transcriptional repression of oncogenes through stabilization of these structures could be a novel anticancer strategy. Many gene promoter G-quadruplexes have physicochemical properties and structural characteristics that might make them druggable, and their structural diversity suggests that a high degree of selectivity might be possible. Here, we describe the evidence for G-quadruplexes in gene promoters and discuss their potential as therapeutic targets, as well as progress in the development of strategies to harness this potential through intervention with small-molecule ligands.

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Figure 1: G-quadruplexes in promoter regions: MYC as an example.
Figure 2: Identification of putative G-quadruplex-forming regions in gene promoters using computational analysis.
Figure 3: Structures of selected G-quadruplex ligands.
Figure 4: G-quadruplexes in the promoter of the gene coding for KIT.
Figure 5: Properties of quarfloxin.

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Acknowledgements

Research in the Hurley laboratory has been supported by grants from the US National Institutes of Health (CA95060, GM085585 and CA122952), the National Foundation for Cancer Research (VONHOFF0601) and the Leukemia & Lymphoma Society (6225-08). Research in the Balasubramanian laboratory has been supported by project grants from the Biotechnology and Biological Sciences Research Council of the UK and programme funding from Cancer Research UK. Research in the Neidle laboratory has been supported by programme funding from Cancer Research UK, and an FP6 grant from the European Union on molecular cancer medicine. We are grateful to T. Brooks for her careful reading of the manuscript and D. Bishop for preparing, proofreading and editing the final version of the text and figures.

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Authors and Affiliations

  1. Shankar Balasubramanian is at the Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK,

    Shankar Balasubramanian

  2. Cancer Research UK, Cambridge Research Institute, Li Ka Shing Center, Cambridge, CB2 0RE, UK,

    Shankar Balasubramanian

  3. Laurence H. Hurley is at the College of Pharmacy, University of Arizona, Tucson, Arizona 85721, USA,

    Laurence H. Hurley

  4. the BIO5 Institute, University of Arizona, Tucson, Arizona 85721, USA,

    Laurence H. Hurley

  5. Stephen Neidle is at the Cancer Research UK Biomolecular Structure Group, the School of Pharmacy, University of London, London, WC1N 1AX, UK,

    Stephen Neidle

  6. the Centre for Cancer Medicines, The School of Pharmacy, University of London, London, WC1N 1AX, UK.,

    Stephen Neidle

  7. the School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0SP, UK.,

    Shankar Balasubramanian

  8. the Arizona Cancer Center, The University of Arizona, Tucson, Arizona 85724, USA.,

    Laurence H. Hurley

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  1. Shankar Balasubramanian
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Laurence H. Hurley is a stockholder in Cylene Pharmaceuticals.

All other authors declare no competing financial interests.

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Balasubramanian, S., Hurley, L. & Neidle, S. Targeting G-quadruplexes in gene promoters: a novel anticancer strategy?. Nat Rev Drug Discov 10, 261–275 (2011). https://doi.org/10.1038/nrd3428

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