Ku-60019

Ataxia-telangiectasia mutated (ATM) is a serine/threonine kinase that activates checkpoint signaling following double strand DNA breaks and genotoxic stress. Ku-60019 is a potent, reversible inhibitor of ATM kinase (IC₅₀ = 6.3 nM), blocking the phosphorylation of ATM substrate proteins.^1,2 It is much less effective or without effect against a panel of 229 other kinases.¹ Ku-60019 sensitizes glioma cells to radiation and inhibits migration and invasion of glioma cells in vitro.^1,2 It produces radiosensitization and increases survival in vivo when administered intra-tumorally in orthotopic xenograft models of glioblastoma multiforme.³ Ku-60019 is particularly effective in producing lethality in cells with mutant p53 or that are deficient in PTEN.^3,4

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1. Golding, S.E., Rosenberg, E., Valerie, N., et al. Improved ATM kinase inhibitor KU-60019 radiosensitizes glioma cells, compromises insulin, AKT and ERK prosurvival signaling, and inhibits migration and invasion. Mol. Cancer Ther. 8(10), 2894-2902 (2009).

2. Golding, S.E., Rosenberg, E., Adams, B.R., et al. Dynamic inhibition of ATM kinase provides a strategy for glioblastoma multiforme radiosensitization and growth control. Cell Cycle 11(6), 1167-1173 (2012).

3. Biddlestone-Thorpe, L., Sajjad, M., Rosenberg, E., et al. ATM kinase inhibition preferentially sensitizes p53-mutant glioma to ionizing radiation. Clin. Cancer Res. 19(12), 3189-3200 (2013).

4. McCabe, N., Hanna, C.D., Walker, S.M., et al. Mechanistic rationale to target PTEN-deficient tumour cells with inhibitors of the DNA damage response kinase ATM. Cancer Res. 75(11), 2159-2165 (2015).