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IC50: KU-0060648 inhibited cellular DNA-PK autophosphorylation with IC50 values of 0.17 μmol/L (SW620 cells) and 0.019 μmol/L (MCF7 cells), and PI-3K–mediated AKT phosphorylation with IC50 values of 0.039 μmol/L (MCF7 cells) and more than 10 μmol/L (SW620 cells).

DNA double-strand breaks (DSB) are the most cytotoxic lesions induced by topoisomerase II poisons. Nonhomologous end joining (NHEJ) is a major pathway for DSB repair and requires DNA-dependent protein kinase (DNA-PK) activity. DNA-PK catalytic subunit (DNA-PKcs), which promotes cell survival and proliferation and is upregulated in many cancers, is structurally similar to PI-3K,. KU-0060648 is a dual inhibitor of DNA-PKand PI-3K in vitro.

In vitro: KU-0060648 was investigated in a panel ofhumanbreast and colon cancer cells. Five-day exposure to 1 μM KU-0060648 was found to inhibite cell proliferation by more than 95% in MCF7 cells but only by 55% in SW620 cells. KU-0060648 increased the etoposide and doxorubicin cytotoxicity across the DNA-PKcs–proficient cell panel rather than in DNA-PKcs–deficient cells, therefore confirming the enhanced cytotoxicity was due to the inhibition of DNA-PK [1].

In vivo: In mice bearing SW620 and MCF7 xenografts, KU-0060648 concentrations that were sufficient for in vitro growth inhibition and chemosensitization were maintained within the tumor at nontoxic doses for at least 4 hours. KU-0060648 alone delayed the MCF7 xenografts growth and increased etoposide-induced tumor growth delay in both in MCF7 and SW620 xenografts by up to 4.5 folds, without causing etoposide toxicity to unacceptable levels [1].

Clinical trial: KU-0060648 is still in pre-clinical development stage and no clinicl trial is ongoing currently.

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