B196
Development of potent water-soluble inhibitors of the DNA-dependent protein kinase (DNA-PK)
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
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 µM), guided the subsequent development of the potent and selective ATP-competitive chromenone NU7441 (DNA-PK IC50 = 30 nM). Structure-activity relationship studies for DNA-PK inhibition by chromenone-derivatives were conducted in conjunction with homology modelling. This approach predicted several positions on the pendant dibenzothiophen-4-yl substituent of NU7441 as tolerant to substitution, without detriment to DNA-PK inhibitory activity. The introduction of suitable functionality (e.g. OH, NH2 CO2H etc) at these positions provided a platform for the synthesis of focussed libraries of compounds bearing water-solubilising amine substituents.
Library synthesis was undertaken employing a solution multiple-parallel approach, by O-alkylation or N-acylation of the appropriately substituted NU7441 derivatives, respectively, followed by reaction with a range of amines to afford the target compounds. These studies resulted in the identification of KU-0060648, which combines high potency as a DNA-PK inhibitor (IC50 = 8.6 nM) with 20-1000 fold selectivity over related PIKK enzyme family members, and good aqueous solubility as an acid salt The further development of KU-0060648 and analogues will be described.
