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].
AZD-7762 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Lkb1-null t2, t4, t5 cells
0-500 nM
4 days
To evaluate the effect of AZD7762 alone or in combination with gemcitabine on the viability of Lkb1-null cells, the results showed that the combination significantly reduced cell viability.
Cancer Res. 2017 Sep 15;77(18):5068-5076.
HT29 cells
100 nM
6 h
To test the efficacy of LMP-400 for inducing a substantial S-phase arrest and the extent to which this arrest could be abrogated by AZD7762, it was found that AZD7762 was able to reactivate DNA synthesis and re-establish a normal cell cycle profile.
Cancer Res. 2012 Feb 15;72(4):979-89.
HT29 cells
16, 31, 63, 125 nM
48 h
To evaluate the potential impact of AZD7762 on LMP-400-induced cell killing, it was found that AZD7762 showed synergistic antiproliferative activity when combined with LMP-400 in HT29 cells.
Cancer Res. 2012 Feb 15;72(4):979-89.
UM-UC-3
20 nM
24 or 48 h
To evaluate the effect of AZD7762 combined with gemcitabine on the viability of bladder cancer cells, the results showed that the combined use significantly reduced cell viability.
J Exp Clin Cancer Res. 2017 Jan 3;36(1):1.
T24
10 nM
24 or 48 h
To evaluate the effect of AZD7762 combined with gemcitabine on the viability of bladder cancer cells, the results showed that the combined use significantly reduced cell viability.
J Exp Clin Cancer Res. 2017 Jan 3;36(1):1.
RT-112
10 nM
24 or 48 h
To evaluate the effect of AZD7762 combined with gemcitabine on the viability of bladder cancer cells, the results showed that the combined use significantly reduced cell viability.
J Exp Clin Cancer Res. 2017 Jan 3;36(1):1.
VM-CUB1
10 nM
24 or 48 h
To evaluate the effect of AZD7762 combined with gemcitabine on the viability of bladder cancer cells, the results showed that the combined use significantly reduced cell viability.
J Exp Clin Cancer Res. 2017 Jan 3;36(1):1.
MiaPaCa-2 cells
100 nM
24 h
To evaluate the chemosensitization effect of AZD-7762 on pancreatic cancer cells, results showed that AZD-7762 significantly enhanced the cytotoxicity of gemcitabine when administered 24 h after gemcitabine treatment.
Clin Cancer Res. 2011 Jun 1;17(11):3706-15.
A549
100 nM
24 h
AZD7762 partially reversed the A-macB-induced G2/M arrest and enhanced the cytotoxicity of A-macB.
Cancer Biol Ther. 2018 Jul 3;19(7):609-621.
H1299
100 nM
24 h
AZD7762 partially reversed the A-macB-induced G2/M arrest and enhanced the cytotoxicity of A-macB.
Cancer Biol Ther. 2018 Jul 3;19(7):609-621.
AZD-7762 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
NOD/SCID mice
Intraperitoneal injection
25 mg/kg
Every 24 and 42 hours
The combination therapy of AZD7762 and irinotecan significantly inhibited tumor growth and prolonged survival in mice bearing TP53 mutant tumors
J Clin Invest. 2012 Apr;122(4):1541-52
Mice
Kras/p53/Lkb1 mice
Intraperitoneal injection
25 mg/kg
Once daily for two weeks
To evaluate the effect of AZD7762 alone or in combination with gemcitabine on tumor volume in Kras/p53/Lkb1 mice, the results showed that the combination significantly reduced tumor volume and prolonged survival.
Cancer Res. 2017 Sep 15;77(18):5068-5076.
Nude mice
Pancreatic cancer xenograft model
Subcutaneous injection
25 mg/kg
Once every 7 days for 14 days
To evaluate the chemosensitization effect of AZD-7762 on pancreatic cancer xenograft models, results showed that AZD-7762 significantly inhibited tumor growth after gemcitabine treatment.
Clin Cancer Res. 2011 Jun 1;17(11):3706-15.
Mice
MiaPaCa-2 xenograft model
Subcutaneous injection
20mg/kg
Administered on days 0, 1, 7, 8, 14, and 15
Evaluate the effect of AZD7762 in combination with gemcitabine and radiation on pancreatic cancer, showing significant tumor regression in the AZD7762+1Gy and GEM+1Gy groups
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