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Targeting DNA-PK as a Therapeutic Approach in Oncology

Lookup NU author(s): Dr Celine Cano, Dr Suzannah Harnor, Dr Elaine Willmore, Professor Steve Wedge

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Abstract

© 2018, Springer International Publishing AG, part of Springer Nature.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.


Publication metadata

Author(s): Cano C, Harnor SJ, Willmore E, Wedge SR

Editor(s): Pollard J; Curtin N

Publication type: Book Chapter

Publication status: Published

Book Title: Targeting the DNA Damage Response for Anti-Cancer Therapy

Year: 2018

Pages: 339-357

Print publication date: 05/06/2018

Online publication date: 27/05/2018

Acceptance date: 02/04/2016

Series Title: Cancer Drug Discovery and Development

Publisher: Humana Press Inc.

Place Published: New York

URL: https://doi.org/10.1007/978-3-319-75836-7_13

DOI: 10.1007/978-3-319-75836-7_13

Library holdings: Search Newcastle University Library for this item

ISBN: 9783319758343


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