PF-04217903

For research use only.

Catalog No.S1094

21 publications

PF-04217903 Chemical Structure

CAS No. 956905-27-4

PF-04217903 is a selective ATP-competitive c-Met inhibitor with IC50 of 4.8 nM in A549 cell line, susceptible to oncogenic mutations (no activity to Y1230C mutant). Phase 1.

Selleck's PF-04217903 has been cited by 21 publications

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Biological Activity

Description PF-04217903 is a selective ATP-competitive c-Met inhibitor with IC50 of 4.8 nM in A549 cell line, susceptible to oncogenic mutations (no activity to Y1230C mutant). Phase 1.
Targets
c-Met [1]
(A549 cells)
4.8 nM
In vitro

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. [1] PF-04217903 in combination with sunitinib significantly inhibits endothelial cells, but not the tumor cells B16F1, Tib6, EL4, and LLC [2] 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. [3] 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. [4]
Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
human A549 cells NFTGPJFHfW6ldHnvckBie3OjeR?= MUGxJIg> MXfBcpRi\2:waYP0JIFkfGm4aYT5JIF1KGNvTVXUJJJm[2WydH;yJIlvKGi3bXHuJGE2PDliY3XscJMh[XO|ZYPz[YQh[XNiaX7obYJqfGmxbjDv[kBifXSxcHjvd5Bpd3K7bHH0bY9vKGGodHXyJFEhcHJiYomgSWxKW0FuIFnDOVA:PCCwTR?= MnTrNlI6OjR5M{S=

... Click to View More Cell Line Experimental Data
In vivo Although 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. [2]

Protocol

Kinase Assay:[1]
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Cellular c-Met phosphorylation ELISA:

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 Research:[2]
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  • Cell lines: B16F1, Tib6, EL4, and LLC, HUVECs and C166 cells
  • Concentrations: Dissolved in DMSO, final concentrations ~2 μM
  • Incubation Time: 4 days
  • Method: 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.
    (Only for Reference)
Animal Research:[2]
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  • Animal Models: Immunodeficient nude mice (nu/nu) subcutaneously implanted with tumor cell lines B16F1, EL4, LLC, or Tib6
  • Dosages: 45 mg/kg
  • Administration: Orally
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 5 mg/mL (13.42 mM)
Water Insoluble
Ethanol Insoluble
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
2% DMSO+30% PEG 300+2% Tween 80+ddH2O
For best results, use promptly after mixing. 		2mg/mL

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 372.38
Formula

C19H16N8O
CAS No. 956905-27-4
Storage powder
in solvent
Synonyms N/A
Smiles C1=CC2=C(C=CC(=C2)CN3C4=NC(=CN=C4N=N3)C5=CN(N=C5)CCO)N=C1

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Clinical Trial Information

NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT00706355 Terminated Drug: PF-04217903 Neoplasms Pfizer August 2008 Phase 1

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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c-Met Signaling Pathway Map

c-Met Inhibitors with Unique Features

  • Non-specific c-Met Inhibitor

    BMS-777607 : C-Met, IC50=3.9 nM；Axl, IC50=1.1 nM; Ron, IC50=1.8 nM; Tyro3, IC50=4.3 nM.

  • Most Potent c-Met Inhibitor

    INCB28060 : C-Met, IC50=0.13 nM.

  • FDA-approved c-Met Inhibitor

    Crizotinib (PF-02341066) : Approved by FDA for non-small cell lung carcinoma (NSCLC).

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  • Crizotinib (PF-02341066)

    Crizotinib (PF-02341066) is a potent inhibitor of c-Met and ALK with IC50 of 11 nM and 24 nM in cell-based assays, respectively. It is also a potent ROS1 inhibitor with Ki value less than 0.025 nM. Crizotinib induces autophagy through inhibition of the STAT3 pathway in multiple lung cancer cell lines.

  • Foretinib (GSK1363089)

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  • Capmatinib (INCB28060)

    Capmatinib (INCB28060, INC280, NVP-INC280) is a novel, ATP-competitive inhibitor of c-MET with IC50 of 0.13 nM in a cell-free assay, inactive against RONβ, as well as EGFR and HER-3. Capmatinib (INCB28060) inhibits Wnt/β-catenin and EMT signaling pathways and induces apoptosis in diffuse gastric cancer positive for c-MET amplification. Phase 1.

    Features:Inactive against RONβ, another member of the c-MET RTK family, as well as EGFR and HER-3 (members of the EGFR RTK family).

  • Tivantinib (ARQ 197)

    Tivantinib (ARQ 197) is the first non-ATP-competitive c-Met inhibitor with Ki of 0.355 μM in a cell-free assay, little activity to Ron, and no inhibition to EGFR, InsR, PDGFRα or FGFR1/4. Tivantinib (ARQ 197) induces a G2/M arrest and apoptosis. Phase 3.

    Features:The first selective c-Met inhibitor to be advanced into human clinical trials.

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  • BMS-777607

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    Features:A potent inhibitor of the Met family, and >40-fold selectivity vs. Lck, VEGFR2, and TrkA/B and >500-fold selective vs. other receptor and non-receptor kinases.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID