PF-04217903

Catalog No.S1094

PF-04217903 Chemical Structure

Molecular Weight(MW): 372.38

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.

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In DMSO USD 160 In stock
USD 110 In stock
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Cited by 8 Publications

4 Customer Reviews

  • (A) p-MET, p-eIF4E, and p-ERK1/2 levels in S462 cells 24 hours after treatment with 1 μM PF04217903 and 750 nM PD901. (B) Change in cell number after treatment with 1 μM PF04217903 (PF903) and/or 750 nM PD901. Graph represents the average log2 of fold change in cell number 72 hours after treatment relative to time 0 (mean ± SD, n = 3).

    J Clin Invest, 2016, 126(6):2181-90. PF-04217903 purchased from Selleck.

    Clonogenicity of LXFA 526L and LXFA 1647L with titration of the MET inhibitor PF-04217903 and combination of PF-04217903 at 0.1 uM with 0.66 uM cetuximab.

    Eur J Cancer 2011 47(8), 1231-43. PF-04217903 purchased from Selleck.

  • MET signaling inhibition attenuated the invasion and metastasis-promoting effects induced by VEGF inhibition in hepa1-6 orthotopic models. Inhibitory effects of VEGF antibody, PF-04217903 alone, and their combination on HCC growth and intrahepatic metastasis in the hepa1-6 orthotopic models. Tumor volumes and numbers of tumor foci in the orthotopic implantation models were measured and quantified.

    J Exp Clin Cancer Res, 2018, 37(1):93. PF-04217903 purchased from Selleck.

    Western blot analysis of c-Met, MAPK and Akt. 0-100nM PF04217903 was added.

     

     

    Dr. Zhang of Tianjin Medical University. PF-04217903 purchased from Selleck.

Purity & Quality Control

Choose Selective c-Met Inhibitors

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 NX62[5o3TnWwY4Tpc44h[XO|YYm= NYn6dmc4OSCq M1XxOmFvfGGpb37pd5Qh[WO2aY\peJkh[XRiYz3NSXQhemWlZYD0c5IhcW5iaIXtZY4hSTV2OTDj[YxteyCjc4Pld5Nm\CCjczDpcohq[mm2aX;uJI9nKGG3dH;wbI9{eGixconsZZRqd25iYX\0[ZIhOSCqcjDifUBGVEmVQTygTWM2OD12IH7N MoXNNlI6OjR5M{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]
+ Expand

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]
+ Expand
  • 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]
+ Expand
  • Animal Models: Immunodeficient nude mice (nu/nu) subcutaneously implanted with tumor cell lines B16F1, EL4, LLC, or Tib6
  • Formulation: Dissolved in DMSO, and diluted in saline
  • 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

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Clinical Trial Information

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT00706355 Terminated 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

Tel: +1-832-582-8158 Ext:3

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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).

  • Newest c-Met Inhibitor

    EMD 1214063 New : Potent and selective c-Met inhibitor with IC50 of 4 nM, >200-fold selective for c-Met than IRAK4, TrkA, Axl, IRAK1, and Mer.

Related c-Met Products4

  • NPS-1034 New

    NPS-1034 is a dual Met/Axl inhibitor with IC50 of 48 nM and 10.3 nM, respectively.

  • Erlotinib New

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  • R428 (BGB324) New

    R428 (BGB324) is an inhibitor of Axl with IC50 of 14 nM, >100-fold selective for Axl versus Abl. Selectivty for Axl is also greater than Mer and Tyro3 (50-to-100- fold more selective) and InsR, EGFR, HER2, and PDGFRβ (100- fold more selective).

  • 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.

  • Foretinib (GSK1363089)

    Foretinib (GSK1363089) is an ATP-competitive inhibitor of HGFR and VEGFR, mostly for Met and KDR with IC50 of 0.4 nM and 0.9 nM in cell-free assays. Less potent against Ron, Flt-1/3/4, Kit, PDGFRα/β and Tie-2, and little activity to FGFR1 and EGFR. Phase 2.

  • Capmatinib (INCB28060)

    Capmatinib (INCB28060) 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. 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. Phase 3.

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

  • PHA-665752

    PHA-665752 is a potent, selective and ATP-competitive c-Met inhibitor with IC50 of 9 nM in cell-free assays, >50-fold selectivity for c-Met than RTKs or STKs.

  • BMS-777607

    BMS-777607 is a Met-related inhibitor for c-Met, Axl, Ron and Tyro3 with IC50 of 3.9 nM, 1.1 nM, 1.8 nM and 4.3 nM in cell-free assays, 40-fold more selective for Met-related targets versus Lck, VEGFR-2, and TrkA/B, and more than 500-fold greater selectivity versus all other receptor and non receptor kinases. Phase 1/2.

    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.

  • SU11274

    SU11274 is a selective Met inhibitor with IC50 of 10 nM in cell-free assays, no effects on PGDFRβ, EGFR or Tie2.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID