The serine/threonine protein kinase ATM signals can regulate cell cycle and DNA repair components through phosphorylation on the targets such as p53, CHK2, NBS1, and BRCA1, thus playing a central role in the maintenance of genome integrity. KU-60019 is an improved inhibitor of the ATM kinase (compared with KU-55933) with an IC50 of 6.3 nM. Pre-treatment with KU-60019 can inhibit the downstream targets p53 phosphorylation at Ser15 site, as well as CHK2 at T68 site, induced by 5Gy of ionizing radiation in U1242 cells. Compared with KU-55933, KU-60019 acts as a more potent radiosensitizer at concentration>1 μM in U87 and U1242 human glioma cells but not A-T fibroblasts. Treatment with KU-60019 resulted in inhibited migration of U87 cells ≥70% in a dose-dependent manner and inhibited invasion of U1242 cells by ∼60%, which may due to the impaired AKT signaling[1]. In in vivo study, combination of radiation and KU-60019 administrated by pump implantation at dose of 10μM, significantly increase survival of mice 2- to 3-fold over controls in orthotopic human glioma xenograft models[2].
作用机制
KU-60019 is an improved form of KU-55933, which is an ATP-competitive ATM inhibitor.[1]
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