AZD7762 hydrochloride is a potent ATP-competitive checkpoint kinase inhibitor with an IC50 of 5 and <10 nM for CHK1 and CHK2 respectively. AZD7762 has been profiled extensively in vitro andin vivo in combination with DNA-damaging agents and has been shown to potentiate response in several different settings where inhibition of checkpoint kinase results in the abrogation of DNA damage-induced cell cycle arrest.
|Cell lines||SW620 and MDA-MB-231 cells line|
|Preparation method||Potentiation Assays.
SW620 (5.5 × 103 per well) or MDA-MB-231 (5 × 103 per well) cells were seeded in 96-well plates and incubated overnight. Cells were dosed for 24 h with a 9-point titration of gemcitabine ranging from 0.01 to 100 nmol/L with or without a constant dose of AZD7762 (300 nmol/L). Control wells were dosed with vehicle alone (0.1% DMSO) or 300 nmol/L AZD7762. After 24 h, medium was removed and AZD7762 alone was added back to the wells treated previously with AZD7762 for an additional 24 h. Cells were then incubated in drug-free medium for an additional 72 h. The effect on cell proliferation was determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethophenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt assay as recommended by the supplier (Promega). The same experimental procedure was used for topotecan combinations (topoisomerase I inhibitor, analogue of camptothecin) except an 11-point titration of topotecan ranging from 0.1 nmol/L to 30 μmol/L was used. Net growth was calculated (AT120 - AT0 / predose) × 100 and plotted versus concentration of chemotherapy in the presence and absence of AZD7762. IC50 values were calculated by concentration-response fitting using four-variable logistical equations (Sigmoidal fit) within Origin Pro.
|Concentrations||0.01 ~ 100 nmol/L|
|Incubation time||48 h|
|Animal models||Xenograft Models in Mice|
|Dosages||50~100mg/kg every 3 days|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 15 mg/mL|
The Chk1 inhibitor AZD7762 sensitises p53 mutant breast cancer cells to radiation in vitro and in vivo.
Ma, et al. Mol Med Report. 2012 Oct;6(4):897-903. PMID: 22825736.
The Checkpoint Kinase Inhibitor AZD7762 Potentiates Chemotherapy-Induced Apoptosis of p53-Mutated Multiple Myeloma Cells.
Landau, et al. Mol Cancer Ther. 2012 Aug;11(8):1781-8. PMID: 22653969.
Discovery of checkpoint kinase inhibitor (S)-5-(3-fluorophenyl)-N-(piperidin-3-yl)-3-ureidothiophene-2-carboxamide (AZD7762) by structure-based design and optimization of thiophenecarboxamide ureas.
Oza, et al. J Med Chem. 2012 Jun 14;55(11):5130-42. PMID: 22551018.
Potentiation of the novel topoisomerase I inhibitor indenoisoquinoline LMP-400 by the cell checkpoint and Chk1-Chk2 inhibitor AZD7762.
Aris, et al. Cancer Res. 2012 Feb 15;72(4):979-89. PMID: 22189968.
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