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    AZD7762
    AZD7762

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V1582
    CAS #: 860352-01-8 (free base)Purity ≥98%

    Description: AZD7762 is a novel, potent, selective and ATP-competitive small molecule inhibitor of Chk1 (checkpoint kinases) with IC50 of 5 nM in a cell-free assay. It is equally potent against Chk2 and less potent against CAM, Yes, Fyn, Lyn, Hck and Lck. AZD7762 prevents cell cycle arrest and DNA repair in DNA damaged tumor cells, causing tumor cell apoptosis. Hence, it potentiates the antitumor activity of DNA damaging agents and can be used as a chemosensitizing agent. Chk1 (checkpoint kinases) are protein kinases that regulate either G1/S or G2/M transitions in the cell cycle. In the presence of DNA damage or incomplete DNA replication, Chks become activated and initiate cell cycle arrest to allow DNA repair or the completion of DNA replication. 

    References: Mol Cancer Ther. 2008 Sep;7(9):2955-66.

    Related CAS:1246094-78-9 (AZD7762 HCl); 860352-01-8 (free base)

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    Molecular Weight (MW)362.42
    FormulaC17H19FN4O2S
    CAS No.860352-01-8
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 50 mg/mL (138.0 mM) 
    Water: <1 mg/mL
    Ethanol: <1 mg/mL
    Other info
    Chemical Name: (S)-5-(3-fluorophenyl)-N-(piperidin-3-yl)-3-ureidothiophene-2-carboxamide
    InChi Key: IAYGCINLNONXHY-LBPRGKRZSA-N
    InChi Code: InChI=1S/C17H19FN4O2S/c18-11-4-1-3-10(7-11)14-8-13(22-17(19)24)15(25-14)16(23)21-12-5-2-6-20-9-12/h1,3-4,7-8,12,20H,2,5-6,9H2,(H,21,23)(H3,19,22,24)/t12-/m0/s1
    SMILES Code: O=C(C1=C(NC(N)=O)C=C(C2=CC=CC(F)=C2)S1)N[[email protected]@H]3CNCCC3 
    SynonymsAZD7762; AZD 7762; AZD-7762


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    In Vitro

    In vitro activity: AZD7762, a more selective Chk1 inhibitor, inhibits Chk1 phosphorylation of a cdc25C peptide by reversibly binding to the ATP-binding site of Chk1, with IC50 of 5 nM and Ki of 3.6 nM. AZD7762 induces cell arrest with EC50 of 0.620 μM, and significantly abrogates the camptothecin induced G2 arrest with an EC50 of 10 nM, by blocking the chk1 dependent degradation of Cdc25A and activation of Cyclin A. AZD7762 (300 nM) enhances the antitumor efficacy of gemcitabine against SW620 and topotecan against MDA-MB-231 by reducing the GI50 values from 24.1 nM and 2.25 μM to 1.08 nM and 0.15 μM, respectively.  AZD7762 shows cytotoxicity against a variety of neuroblastoma cell lines bearing p53 wild type, p53 mutation, Mdm2 amplification or p14 deletion with IC50 values ranging from 82.6-505.9 nM.


    Kinase Assay: Recombinant human Chk1 is expressed as a glutathione S-transferase fusion in insect cells using a baculovirus vector and purified by glutathione affinity chromatography. A synthetic peptide substrate (N-biotinylaminohexanoyl-KKVSRSGLYRSPMPENLNRPR) for Chk1 is synthesized. Final assay concentrations of peptide and ATP (cold + 40 nCi [33P]ATP) are 0.8 and 1 μM, respectively. Different concentrations of AZD7762, buffer containing peptide and chk1 kinase and ATP, are added sequentially to a 384-well assay plate. The plate is incubated for 2 hours, reaction is stopped by the addition of buffer containing EDTA and scintillation proximity assay beads, and plates are read using a TopCount reader. Data analysis is carried out to determinate a dose response (IC50).


    Cell Assay: For the checkpoint abrogation assay, HT29 cells are treated for 2 hours with camptothecin (topoisomerase I inhibitor; 0.07 μg/mL) to induce the G2 checkpoint. Cells are then treated for 20 hours with a 12-point titration of AZD7762 (12.5 μM to 6 nM) plus nocodazole. Cells are fixed with 3.7% formaldehyde for 1 hour, permeabilized with PBS containing 0.05% Triton X, and incubated with anti-phH3 antibody for 1 hour followed by Alexa Fluor 488 anti-rabbit and Hoechst stain for 1 hour. Mitotic index is determined on the ArrayScan and expressed as the percentage of cells undergoing mitosis. For the potentiation assays, SW620 or MDA-MB-231 cells are dosed for 24 hours with a 9-point titration of gemcitabine ranging from 0.01 to 100 nM with a constant dose of AZD7762 (300 nM). After 24 hours, medium is removed and AZD7762 alone is added back to the wells for an additional 24 hours. Cells are then incubated in AZD7762-free medium for an additional 72 hours. The effect on cell proliferation is determined by MTT.

    In VivoAZD7762 alone at 25 mg/kg shows little antitumor activity in the H460-DNp53 xenograft mice and SW620 xenograft mice, but when administrated in combination with gemcitabine (60 mg/kg), AZD7762 shows significant antitumor efficacy in the two xenografts mice with a log cell kill of 0.9 or percent treated/control (%T/C) of 26 even at low dose of 12.5 mg. Dosing of AZD7762 in combination with gemcitabine (10 mg/kg) in the H460-DNp53 xenograft rat inhibits the tumor volume in a dose-dependent manner with the %T/C values of 48 and 32 for 10 and 20 mg/kg AZD7762, respectively. AZD7762 (25 mg/kg) in combination with irinotecan (25 or 50 mg/kg) causes complete tumor regression in the SW620 xenograft mice with the %T/C increasing significantly to -66% and -67%, respectively.
    Animal modelMale NCr mice implanted s.c. with H460-DNp53 cells or SW620, and male rnu rats implanted s.c. with H460-DNp53 cells
    Formulation & DosageFormulated in 11.3% hydroxyproplyl-β-cyclodextrin; 25 mg/kg; i.v. injection
    References

    Mol Cancer Ther. 2008 Sep;7(9):2955-66.


    These protocols are for reference only. InvivoChem does not independently validate these methods.

     

    AZD7762

     

    AZD7762

     

    AZD7762

     AZD7762


    Effect of AZD7762 on cell cycle proteins following treatment of cells with DNA-damaging agents.  2008 Sep;7(9):2955-66.

     AZD7762


    AZD7762 potentiated gemcitabine and topotecan.  2008 Sep;7(9):2955-66.

     AZD7762


    AZD7762 potentiated gemcitabine in rodent xenograft efficacy models.  2008 Sep;7(9):2955-66.


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