生物活性

• 靶点

  Chk1 IC50:5nM

  Chk2 IC50:5nM

• 描述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].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  22RV1	-	Growth Inhibition Assay	-	IC50=1.80853 μM	SANGER
  23132-87	-	Growth Inhibition Assay	-	IC50=0.68306 μM	SANGER
  5637	-	Growth Inhibition Assay	-	IC50=0.19278 μM	SANGER

• 更多

• 动物研究
  剂量	Rat[1] (i.v.): 10 mg/kg, 20 mg/kg
  给药途径	i.v.
  动物药代数据	Animal Mice[3] Dose 3 mg/kg Administration i.v. K21 0.57 V1/F 4.3 L/kg K12 0.46 K10 0.59

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00413686	Solid Tumors	Phase 1	Completed	-	United States, Maryland ... more >> Research Site Baltimore, Maryland, United States United States, Michigan Research Site Detroit, Michigan, United States Collapse <<
  NCT00937664	Cancer Solid ... more >>Tumors Advanced Solid Malignancies Collapse <<	Phase 1	Terminated(Termination of the ... more >>study was made after a full review of program data and assessment of the current risk-benefit profile.) Collapse <<	February 2011	Japan ... more >> Research Site Minami-ku, Fukuoka, Japan Collapse <<
  NCT00473616	Advanced Solid Tumors ... more >> Cancer Advanced Solid Malignancies Collapse <<	Phase 1	Terminated(Termination of the ... more >>study was made after a full review of program data and assessment of the current risk-benefit profile.) Collapse <<	-	United States, Massachusetts ... more >> Research Site Boston, Massachusetts, United States United States, New York Research Site New York, New York, United States United States, Tennessee Research site Nashville, Tennessee, United States Collapse <<

• 参考文献

• [1] Zabludoff SD, Deng C, et al. AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies. Mol Cancer Ther. 2008 Sep;7(9):2955-66.

  [2] Matthews TP, Jones AM, et al. Structure-based design, discovery and development of checkpoint kinase inhibitors as potential anticancer therapies. Expert Opin Drug Discov. 2013 Jun;8(6):621-40.

  [3] Goteti K, Garner CE, et al. Preclinical pharmacokinetic/pharmacodynamic models to predict synergistic effects of co-administered anti-cancer agents. Cancer Chemother Pharmacol. 2010 Jul;66(2):245-54.