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.
|Source||J Natl Cancer Inst (2017). Figure 3. AZD7762|
|Method||Effects of carbamoyl phosphate synthetase 1 (CPS1) knockdown|
|Cell Lines||LKB1-intact cell line|
|Results||We examined the effects of CPS1 knockdown combined with gemcitabine and pemetrexed, which interfere with DNA synthesis pathways and are frequently used to treat LADC, as well as with CHK1 inhibitor AZD7762, to which LKB1-deficient lung cancer was recently shown to be sensitive|
|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 Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
|Solubility||DMSO 15 mg/mL|
 Oza, et al. J Med Chem. 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.
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