Development of potent water-soluble inhibitors of the DNA-dependent protein kinase (DNA-PK)


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Celine Cano1, Nicola Curtin1, Bernard Golding1, Karen Haggerty1, Ian Hardcastle1, Marc Hummersone2, Keith Menear2, Caroline Richardson2, Graeme Smith2, Roger Griffin1

1Northern Institute for Cancer Research, Newcastle Upon Tyne, UK, 2KuDOS Pharmaceuticals Ltd, Cambridge, UK

Abstract

Development of potent water-soluble inhibitors of the DNA-dependent protein kinase (DNA-PK)

The cellular response to DNA double-strand break (DSB) formation is an essential component of normal cell survival, following exposure to DNA-damaging chemicals (e.g. cisplatin and doxorubicin) and ionising radiation. The serine/threonine kinase DNA-dependent protein kinase (DNA-PK) is a member of the phosphatidylinositol (PI) 3-kinase related kinase (PIKK) family of enzymes, and plays an important role in DNA DSB repair via the non-homologous end-joining (NHEJ) pathway. DNA-PK inhibitors may, therefore, be useful as agents to improve the activity of radio- and chemo-therapy in the treatment of cancer.

Identification of the lead benzo[h]chromen-4-one DNA-PK inhibitor NU7026 (IC50 = 0.23