The Chk (checkpoint kinase) can transiently delay the cell cycle progression through the G1, S, or the G2 phases to ensure that DNA can be efficiently repaired. The activation of Chk1 and Chk2 requires activated ATR and ATM kinases. The G1 checkpoint is predominantly regulated by the ATM/Chk2 pathway, while the S and G2 checkpoints are regulated by the ATR/Chk1 pathway. AZD7762 is a dual inhibitor for both Chk1 and Chk2 kinases with IC50 values of 5 nM and <10 nM (measured by a scintillation proximity assay), respectively. AZD7762 can abrogate the checkpoint cell cycle arrest mediated by DNA-damaging agents. Treatment with 30 - 500 nM AZD7762 for 8h can stabilize the cdc25A (a direct substrate negatively regulated by Chk1) level dose-dependently in SW620 cells arrested by 0.1 μM gemcitabine at the S checkpoint. Consistent with the inhibition of the checkpoint kinase, the level of phospho-cdc2-Tyr15 (a substrate phosphorylated and inactivated by checkpoint kinase) decreased dose-dependently, after release from G2 checkpoint induced by SN-38, in SW620 cells combined treatment with 30 - 500 nM AZD7762 for 8h and followed by 22h washout. Combined treatment with 300 nM AZD7762 for 24h can potentiated the activity of gemcitabine and topotecan in p53-mutant SW620 colon cancer cells and MDA-MB-231 breast carcinoma cells, as well as p53-null HCT116 cells. Consistent with this, intravenous treatment of AZD7762 at dose of 25 mg/kg, in combination with gemcitabine, every 3 days with multiple cycles, showed significant antitumor activity compared with either agent alone in athymic mice bearing established H460-DNp53 or SW620 tumors (73% - 77% inhibition), which indicated that AZD7762 can potentiate the tumor efficacy of DNA damaging chemotherapy in vivo[1]. Up to now, a phase I study of AZD7762 has been completed in solid tumors alone and in combination with gemcitabine[2].
作用机制
AZD7762 binds in the ATP-binding site of Chk1 and competes directly for ATP binding in a reversible manner[1].
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