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    PF-477736 (PF-00477736)
    PF-477736 (PF-00477736)

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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 #: V1586
    CAS #: 952021-60-2 Purity ≥98%

    Description: PF-477736 (also known as PF-736, PF-00477736) is a novel, selective, potent and ATP-competitive Chk1 inhibitor with Ki of 0.49 nM in a cell-free assay and also inhibits VEGFR2, Aurora-A, FGFR3, Flt3, Fms (CSF1R), Ret and Yes. It shows ~100-fold selectivity for Chk1 than Chk2. By overriding the last checkpoint defense against DNA damaging agent-induced lethal damage, chk1 inhibitor PF-477736 may potentiate the antitumor efficacy of various chemotherapeutic agents against tumor cells with intrinsic checkpoint defects. 

    References: Mol Cancer Ther. 2008 Aug;7(8):2394-404; Clin Cancer Res. 2009 Jul 15;15(14):4630-40.

    Related CAS#: 1175132-90-7 (HCl); 1071848-28-6; 952238-93-6 (xHCl); 1247874-19-6 (2HCl); 952021-60-2  (free base)

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    Molecular Weight (MW)419.48
    FormulaC22H25N7O2
    CAS No.952021-60-2 (free base); 
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 6 mg/mL (14.3 mM)
    Water: <1 mg/mL
    Ethanol: <1 mg/mL
    Solubility (In vivo)2% DMSO+40% PEG 300: 5 mg/mL 
    SynonymsPF-736,PF-00477736; PF-00477736; PF 00477736; PF00477736; PF-477736; PF 477736; PF477736


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    In Vitro

    In vitro activity: PF-477736 (128 nM) abrogates the camptothecin-induced DNA damage checkpoint in a dose-dependent manner in CA46 and HeLa cells. PF-477736 effectively abrogates the gemcitabine-induced S-phase arrest with a corresponding increase in apoptotic cell populations in HT29 cells. PF-477736 (540 nM) enhances gemcitabine-induced cytotoxicity in a time- and dose-dependent manner in HT29 cells. PF-477736 potentiates the growth-inhibitory activity of a panel of chemotherapeutic agents across a broad spectrum of p53-deficient human cancer cell lines in the MTT assay. Addition of PF-477736 (360 nM) to gemcitabine-arrested cells induces a dramatic increase in the intensity of H2AX phosphorylation, reflecting a greater number of γ-H2AX molecules near sites of DNA damage. PF-477736 (0.5 nM) selectively blocks p73 and P53 phosphorylation in presence of curcumin in HL-60 cells. PF-477736 (360 nM) suppresses docetaxel-induced phosphorylation of histone H3 (Ser10) and Cdc25C (Ser216) and potentiates apoptosis in COLO205 cells. PF-477736 (250 nM) combined with MK-1775 has marked synergistic cytotoxic activity in OVCAR-5 cells. PF-477736 (250 nM) combined with MK-1775 causes accumulation of cells with a DNA content between 2N and 4N in OVCAR-5 cells. PF-477736 (250 nM) combined with MK-1775 causes premature mitosis before the end of DNA replication, with damaged DNA leading to apoptotic cell death in OVCAR-5 cells.


    Kinase Assay: The assay is performed in a 96-well plate for 20 minutes at 30℃ in 0.1 mL of assay buffer containing 50 mM TRIS pH 7.5, 0.4 M NaCl, 4 mM PEP, 0.15 mM NADH, 28 units of lactate dehydrogenase/mL, 16 units of pyruvate kinase/mL, 3 mM DTT, 0.125 mM Syntide-2, 0.15 mM ATP and 25 mM magnesium chloride. Assays are initiated with 1 nM of CHK1 kinase domain. The inhibition of CHK1 activity is determined by measuring initial velocities in the presence of varying concentrations of PF-477736. The data is analyzed using Enzyme Kinetic and Excel software and fit to a kinetic model for competitive inhibition to obtain a Ki value. The kinase selectivity of PF-477736 is evaluated by screening the compound at 1 μM or 10 μM against a panel 2 of about 100 protein kinases.


    Cell Assay: The IC50 assay measures the antiproliferative effects of PF-477736 on p53-defective human cancer cell lines. Cells in each line are seeded in complete medium at an exponentially growing density in 96-well assay plate and allowed to attach for 16 hours. Serial dilutions of PF-477736 are then done, and appropriate controls are added to each plate. Cells are incubated with drug for 96 hours. After incubation, MTT working stock diluted in complete medium is added to each well, and cells are incubated for 4 hours. After centrifugation and supernatant removal, DMSO is added to each well and plates are read on SpectraMax plate reader at 540 nm.

    In VivoPF-477736 (4 mg/kg i.v.) results in terminal half-life (T1/2) of 2.9 hours, AUC of 5.72 μg×hr/mL and CLp of 11.8 mL/min/kg in rats. PF-477736 dose-dependently enhances the antitumor activity of a maximum tolerated dose of gemcitabine in the Colo205 xenograft mouse model. PF-477736 (12 mg/kg) induces an increase in the phosphorylation of histone H3 (Ser10) and of phospho-histone H2AX in the Colo205 xenograft mouse model. PF-477736 (15 mg/kg i.p.) enhances docetaxel induced tumor growth inhibition and tumor growth delay in COLO205 and MDA-MB-231 xenograft models. PF 477736 (10 mg/kg once daily i.p.) combined with MK-1775 (30 mg/kg twice a day oral) leads to greater tumor growth inhibition in mice bearing OVCAR-5 xenografts.
    Animal modelColo205 xenograft mouse model
    Formulation & DosageDissolved in 50 nM sodium acetate buffer and 4% dextrose (pH 4); 40 mg/kg; i.v. injection
    References

    Mol Cancer Ther. 2008 Aug;7(8):2394-404; Clin Cancer Res. 2009 Jul 15;15(14):4630-40.


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

    PF-477736

    PF-00477736 abrogates the camptothecin-induced DNA damage checkpoint in a dose-dependent manner.  2008 Aug;7(8):2394-404.

     

    PF-477736

    PF-00477736 effectively abrogates the gemcitabine-induced S-phase arrest with a corresponding increase in apoptotic cell populations in the combination treatment compared with the gemcitabine treatment alone.  2008 Aug;7(8):2394-404.

     

    PF-477736

    A, PF-00477736 enhances gemcitabine-induced cytotoxicity in a time- and dose-dependent manner in HT29 cells as determined by cell survival assay.

     

    PF-477736

    A, PF-00477736 potentiates the antiproliferative effect of gemcitabine.  B, in vitro cytotoxicity of PF-00477736 in selected cell lines with different DNA-damaging agents.  2008 Aug;7(8):2394-404.

     

    PF-477736

    A, in vitro effects of gemcitabine ± PF-00477736 on the modulation of proteins involved in the G2 DNA damage checkpoint pathway. B,gemcitabine + PF-00477736 combination in vitro leads to increased DNA damage.

     PF-477736


    A, PF-00477736 potentiation of gemcitabine in human colon Colo205 xenograft model. B, summary of PF-00477736 potentiation of gemcitabine in human colon xenograft models. 2008 Aug;7(8):2394-404


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