AZD7762 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||H29 cells|
|Preparation method||Checkpoint Abrogation Assay
HT29 cells (3 × 105) were seeded in 96-well plates and incubated overnight. Cells were treated for 2 h with camptothecin (topoisomerase I inhibitor; 0.07 μg/mL) to induce the G2 checkpoint. Cells were then treated for 20 h with vehicle (0.5% DMSO) or caffeine (4 mmol/L; positive control) plus nocodazole (1 μg/mL) or a 12-point titration of AZD7762 (12.5 μmol/L to 6 nmol/L) plus nocodazole. Nocodazole alone-treated cells with no camptothecin pretreatment were used to determine the maximum mitotic index. Cells were fixed with 3.7% formaldehyde for 1 h, permeabilized with PBS containing 0.05% Triton X, and incubated with anti-phH3 antibody for 1 h followed by Alexa Fluor 488 anti-rabbit (Molecular Probes) and Hoechst stain for 1 h. Mitotic index was determined on the ArrayScan and expressed as the percentage of cells undergoing mitosis. The EC50 was calculated by concentration-response curve fitting using three-variable logistical equations within XLfit (model 205) with the curve bottom constrained to 0 and the top constrained to 100 by nocodazole alone treatment.
|Incubation time||20 h|
|Animal models||athymic mice bearing established H460-DNp53 or SW620 tumors and rnu rats bearing established H460-DNp53 tumors|
|Formulation||formulated in 11.3% hydroxyproplyl-β-cyclodextrin|
|Dosages||25mg/kg(mouse) and 10 or 20mg/kg (rat)|
|Administration||i.v. injection via the tail vein|
|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.
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.
AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies.
Zabludoff SD, et al. Mol Cancer Ther. 2008 Sep;7(9):2955-66. PMID: 18790776.
|Related Checkpoint Products|
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CCT241533 is a potent serine/threonine checkpoint kinase (Chk2) inhibitor with IC50 of 3 nM.
BML-277 is a high efficient Chk2 inhibitors, IC50 is 15 nM.
AZD7762 hydrochloride is a potent ATP-competitive checkpoint kinase inhibitor with an IC50 of 5 and <10 nM for CHK1 and CHK2 respectively.
CHIR-124 is a novel and potent Chk1 inhibitor with IC50 of 0.3 nM.
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