Ku-0060648

Ku-0060648 is an ATP-competitive inhibitor of DNA-dependent protein kinase (DNA-PK) and an inhibitor of PI3K. In a cell-free assay, it has IC₅₀s of 5, 4, 0.5, <0.1, and 594 nM for DNA-PK, PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ, respectively.¹ In cells, the level of PI3K inhibition is variable, depending upon the cell line utilized. In MCF-7 cells, it has IC₅₀s of 19 and 39 nM, for DNA-PK and PI3K, respectively, while in SW620 cells, it has an IC₅₀ of 170 nM for DNA-PK but >10,000 nM for PI3K.¹ Ku-0060648 is useful for Cas9 editing due to its DNA-PK inhibition, which reduces the frequency of non-homologous end joining and increases homology-directed recombination.² It also shows promise in cancer research in vitro and in vivo.^3,4

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1. Munck, J.M., Batey, M.A., Zhao, Y., et al. Chemosensitization of cancer cells by KU-0060648, a dual inhibitor of DNA-PK and PI-3K. Mol. Cancer Ther. 11(8), 1789-1798 (2012).

2. Robert, F., Barbeau, M., Éthier, S., et al. Pharmacological inhibition of DNA-PK stimulates Cas9-mediated genome editing. Genome Med. 7, 93 (2015).

3. Chen, M.-B., Zhou, Z.-T., Yang, L., et al. KU-0060648 inhibits hepatocellular carcinoma cells through DNA-PKcs-dependent and DNA-PKcs-independent mechanisms. Oncotarget 7(13), 17047-17059 (2016).

4. Lan, T., Zhao, Z., Qu, Y., et al. Targeting hyperactivated DNA-PKcs by KU0060648 inhibits glioma progression and enhances temozolomide therapy via suppression of AKT signaling. Oncotarget 7(34), 55555-55571 (2016).