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Targeting DNA-PK as a Therapeutic Approach in Oncology

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Targeting the DNA Damage Response for Anti-Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Abstract

DNA-dependent protein kinase (DNA-PK) is a nuclear serine/threonine protein kinase member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family of enzymes and, once activated, is a key participant in the repair of DNA-double strand breaks (DSBs), playing a central role in non-homologous end joining (NHEJ).

There have been significant efforts to identify small molecule catalytic inhibitors of DNA-PK, predominantly as an approach to induce chemo- and radio-sensitisation. The catalytic inhibitors described to date, differ in their potency, selectivity and the reversibility of inhibition. These inhibitors have been established from varied chemical structures that includes use of arylmorpholine, benzaldehde, chromen-4-one and indolin-2-one scaffolds. Clinical exploitation of DNA-PK inhibition in combination with DNA-damaging therapies may require strategies to maximize the likelihood of attaining an increased therapeutic index, such as the use of appropriate biomarker strategies to guide inhibitor dose and schedule, localisation of genotoxin treatment, or the elucidation of additional determinants of tumour sensitivity. M-3814 and VX-984 (M-9831) are examples of DNA-PK catalytic inhibitors that have advanced into clinical development, and which may help to determine whether such an approach represents a plausible therapeutic strategy for cancer therapy.

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Authors and Affiliations

  1. Northern Institute for Cancer Research, Newcastle University, School of Chemistry, Newcastle upon Tyne, UK

    Celine Cano & Suzannah J. Harnor

  2. Northern Institute for Cancer Research, Newcastle University, Medical School, Newcastle upon Tyne, UK

    Elaine Willmore & Stephen R. Wedge

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  1. Celine Cano
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  2. Suzannah J. Harnor
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  3. Elaine Willmore
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  4. Stephen R. Wedge
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Correspondence to Stephen R. Wedge .

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  1. Vertex Pharmaceuticals (Europe) Ltd, Abingdon, Oxfordshire, United Kingdom

    John Pollard

  2. Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom

    Nicola Curtin

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Cano, C., Harnor, S.J., Willmore, E., Wedge, S.R. (2018). Targeting DNA-PK as a Therapeutic Approach in Oncology. In: Pollard, J., Curtin, N. (eds) Targeting the DNA Damage Response for Anti-Cancer Therapy. Cancer Drug Discovery and Development. Humana Press, Cham. https://doi.org/10.1007/978-3-319-75836-7_13

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