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    PF-04217903
    PF-04217903

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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 #: V0603
    CAS #: 956905-27-4Purity ≥98%

    Description: PF-04217903 (PF04217903) is an orally bioavailabe and ATP-competitive small-molecule inhibitor of the tyrosine kinase c-Met with potential antitumor activity. It inhibits c-Met with an IC50 of 4.8 nM in A549 cell line. It shows high in vivo antitumor efficacy in nude mice bearing B16F1, EL4, LLC, or Tib6 tumors.

    References: Biochemistry. 2009;48(23):5339-49; Cancer Res. 2010;70(24):10090-100; Eur J Cancer. 2011;47(8):1231-43. 

    Related CAS: 956906-93-7 (mesylate); 956905-27-4 (free base);

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    Molecular Weight (MW)372.38
    FormulaC19H16N8O
    CAS No.956905-27-4 (free base);
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 5 mg/mL (13.4 mM)
    Water: <1 mg/mL
    Ethanol: <1 mg/mL
    Solubility (In vivo)1% DMSO+30% polyethylene glycol+1% Tween 80: 30 mg/mL 
    SynonymsPF04217903; PF4217903; PF-4217903; PF 04217903; PF-04217903; PF 4217903 

    Chemical Name: 2-(4-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol

    InChi Key: PDMUGYOXRHVNMO-UHFFFAOYSA-N

    InChi Code: InChI=1S/C19H16N8O/c28-7-6-26-12-15(9-22-26)17-10-21-18-19(23-17)27(25-24-18)11-13-3-4-16-14(8-13)2-1-5-20-16/h1-5,8-10,12,28H,6-7,11H2

    SMILES Code: OCCN1N=CC(C2=CN=C3C(N(CC4=CC=C5N=CC=CC5=C4)N=N3)=N2)=C1


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    In Vitro

    In vitro activity: Being more selective than staurosporine or PF-02341066, PF-04217903 displays >1000-fold selectivity for c-Met over a panel of 208 kinases, although more susceptible to oncogenic mutations of c-Met that attenuate potency than PF-02341066. In addition to WT c-Met, PF-04217903 displays similar potency to inhibit the activity of c-Met-H1094R, c-Met-R988C, and c-Met-T1010I with IC50 of 3.1 nM, 6.4 nM, and 6.7 nM, respectively, but has no inhibitory activity against c-Met-Y1230C with IC50 of >10 μM. PF-04217903 in combination with sunitinib significantly inhibits endothelial cells, but not the tumor cells B16F1, Tib6, EL4, and LLC PF-04217903 significantly inhibits the clonogenic growth of LXFA 526L and LXFA 1647L with IC50 values of 16 nM, and 13 nM, respectively, yielding an additive effect when in combination with cetuximab. PF-04217903 potently inhibits c-Met-driven processes such as cell growth, motility, invasion, and morphology of a variety of tumor cells. PF-04217903 treatment (2 μM) increased cell death of GTL-16 cells, which involves the downregulation of phosphorylated 4E-BP1, ERK/MAPK associated proteins and PI3K/AKT pathway.


    Kinase Assay: A549 cells with endogenous human WT c-Met are seeded in 96-well plates in growth medium and cultured overnight. On the second day of the assay, the growth medium is replaced with serum-free medium (with 0.04% BSA). Serial dilutions of PF-04217903 are added to each well, and cells are incubated at 37 °C for 1 hour. Then 40 ng/mL HGF is added to the cells for 20 minutes. The cells are washed once with HBSS supplemented with 1 mM Na3VO4, and protein lysates are generated from cells using lysis buffer. Phosphorylation of c-Met is assessed by an ELISA method utilizing capture antibodies specific for c-Met and a detection antibody specific for phosphorylated tyrosine residues. Antibody-coated plates are incubated in the presence of protein lysates at 4 °C overnight and washed with 1% Tween 20 in PBS seven times. HRP-PY20 (horseradish peroxidase-conjugated anti-phosphotyrosine) is diluted 1:500 in blocking buffer and added to each plate for 30 minutes. Plates are then washed again, and TMB peroxidase substrate is added to initiate the HRP-dependent colorimetric reaction and the reaction stopped by addition of 0.09 N H2SO4. ELISA end points are the absorbance measured at 450 nm using a spectrophotometer. IC50 value is calculated by concentration-response curve fitting utilizing a Microsoft Excel-based four-parameter analytical met.


    Cell Assay:  Cells (B16F1, Tib6, EL4, and LLC, HUVECs and C166 cells) are treated with different concentrations PF-04217903 for 4 days. Cell proliferation is assessed by counting content of each well using a Coulter counter machine.

    In VivoAlthough unable to inhibit tumor growth in the sunitinib-sensitive B16F1 and Tib6 tumor models, the combination of PF-04217903 and sunitinib significantly inhibits tumor growth in sunitinib-resistant EL4, and LLC tumor models compared with sunitinib or PF-04217903 alone by significantly blocking vascular expansion, indicating a functional role for HGF/c-Met axis in the sunitinib-resistant tumors.
    Animal modelNude mice (nu/nu) bearing B16F1, EL4, LLC, or Tib6 tumors
    Formulation & DosageDissolved in DMSO; 45mg/kg; p.o.
    References

    Biochemistry. 2009 Jun 16;48(23):5339-49; Cancer Res. 2010 Dec 15;70(24):10090-100; Eur J Cancer. 2011 May;47(8):1231-43. 


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

    PF-04217903

    Endothelial cells, but not tumor cells, are mainly targeted by HGF/c-Met axis.  2010 Dec 15;70(24):10090-100.

    PF-04217903

    Combination of sunitinib and PF-04217903 has additive effect compared with sunitinib monotherapy. Efficacy of combination treatment (sunitinib plus PF-04217903) in sensitive or resistant tumors.  2010 Dec 15;70(24):10090-100. 

    PF-04217903

    Inhibition of angiogenesis is one of the mechanisms by which combination treatment affects tumor growth.  2010 Dec 15;70(24):10090-100. 


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