PF-04217903

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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PF-04217903 Chemical Structure

PF-04217903 Chemical Structure
Molecular Weight: 372.38

Validation & Quality Control

Customer Product Validation(2)

Quality Control & MSDS

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Product Information

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  • Research Area
  • PF-04217903 Mechanism

Product Description

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)
IC50 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]
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]
Features

Protocol(Only for 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 Assay: [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 Study: [2]

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

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Timofeevski SL, et al. Biochemistry, 2009, 48(23), 5339-5349.

[2] Shojaei F, et al. Cancer Res, 2010, 70(24), 10090-10100.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2015-08-29)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT00706355 Terminated Neoplasms Pfizer August 2008 Phase 1

Chemical Information

Download PF-04217903 SDF
Molecular Weight (MW) 372.38
Formula

C19H16N8O

CAS No. 956905-27-4
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 5 mg/mL (13.42 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 1% DMSO/30% polyethylene glycol/1% Tween 80 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* 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 Name 2-(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)-1H-pyrazol-1-yl)ethanol

Customer Product Validation (2)


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Rating
Source Eur J Cancer 2011 47(8), 1231-43. PF-04217903 purchased from Selleck
Method Clonogenic assays
Cell Lines LXFA 526L, LXFA 1647L cells
Concentrations 0-10 uM
Incubation Time 4-5 days
Results The MET inhibitor PF-04217903, with an IC50 of 16 nM and 13 nM could antagonize Clonogenic growth of LXFA 526L and LXFA 1647L. An additive effect of the MET inhibitor with cetuximab was found for both cell lines and was more pronounced for LXFA 526L.

Click to enlarge
Rating
Source Dr. Zhang of Tianjin Medical University. PF-04217903 purchased from Selleck
Method Western blot
Cell Lines MDA-MB-231 cells
Concentrations 0-100 nM
Incubation Time
Results PF-04217903 treatment resulted in a reduction of c-Met, AKT and MAPK phosphorylation in MDA-MB-231 cells.

Product Use Citation (6)

Tech Support & FAQs

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