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PF-04217903

Name: PF-04217903
Brand: Selleck Chemicals
SKU: S1094
Rating: 5 (21 reviews)

Catalog No.S1094

For research use only.

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.

CAS No. 956905-27-4

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

Purity & Quality Control

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c-Met Signaling Pathway Map

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	NYXvc3lYTnWwY4Tpc44h[XO\|YYm=		MUixJIg>		M1fFcGFvfGGpb37pd5Qh[WO2aY\peJkh[XRiYz3NSXQhemWlZYD0c5IhcW5iaIXtZY4hSTV2OTDj[YxteyCjc4Pld5Nm\CCjczDpcohq[mm2aX;uJI9nKGG3dH;wbI9{eGixconsZZRqd25iYX\0[ZIhOSCqcjDifUBGVEmVQTygTWM2OD12IH7N	M2\iPVIzQTJ2N{O0

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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 (from reference)

Kinase Assay:^[1]	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]	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.
Animal Research:^[2]	Animal Models: Immunodeficient nude mice (nu/nu) subcutaneously implanted with tumor cell lines B16F1, EL4, LLC, or Tib6 Dosages: 45 mg/kg Administration: Orally

References

[4] Dillon R, et al. J Proteome Res, 2011, 10(11), 5084-5094.

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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. Click to purchase: PEG300 Tween 80	2mg/mL

Chemical Information

Molecular Weight	372.38
Formula	C₁₉H₁₆N₈O
CAS No.	956905-27-4
Storage	3 years	-20°C	powder
Storage	2 years	-80°C	in solvent
Smiles	C1=CC2=C(C=CC(=C2)CN3C4=NC(=CN=C4N=N3)C5=CN(N=C5)CCO)N=C1

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In vivo Formulation Calculator (Clear solution)

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Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH₂O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

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Molarity Calculator

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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

(data from https://clinicaltrials.gov, updated on 2022-01-17)

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