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Purity: ≥98%
PF-04217903 (PF04217903) is an orally bioavailabe and ATP-competitive small-molecule inhibitor of the tyrosine kinase c-Met with potential antitumor activity. In the A549 cell line, it inhibits c-Met with an IC50 of 4.8 nM. When tested on nude mice with tumors of B16F1, EL4, LLC, or Tib6, it demonstrates a high in vivo antitumor efficacy.
| Targets |
c-Met (Ki = 4.8 nM)
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|---|---|
| ln Vitro |
PF-04217903 exhibits >1000-fold selectivity for c-Met over a panel of 208 kinases, making it more selective than staurosporine or PF-02341066.However, it is more vulnerable to c-Met oncogenic mutations that reduce potency than PF-02341066. With IC50 values of 3.1 nM, 6.4 nM, and 6.7 nM, respectively, PF-04217903 exhibits comparable potency to WT c-Met in inhibiting the activity of c-Met-H1094R, c-Met-R988C, and c-Met-T1010I. However, it lacks inhibitory activity against c-Met-Y1230C, as evidenced by an IC50 value of >10 μM.[1] When combined with sunitinib, PF-04217903 significantly inhibits endothelial cells, but not LLC, B16F1, Tib6, EL4, or tumor cells.[2] The clonogenic growth of LXFA 526L and LXFA 1647L is significantly inhibited by PF-04217903, with IC50 values of 16 nM and 13 nM, respectively. This combination with cetuximab produces an additive effect.[3] The morphology, motility, growth, and invasion of various tumor cells are among the c-Met-driven processes that PF-04217903 potently inhibits. ERK/MAPK associated proteins, the PI3K/AKT pathway, and phosphorylated 4E-BP1 were all downregulated in GTL-16 cells upon treatment with PF-04217903 (2 μM).[4]
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| ln Vivo |
PF-04217903 plus 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, suggesting a functional role for the HGF/c-Met axis in the sunitinib-resistant tumors, even though it is unable to inhibit tumor growth in the sunitinib-sensitive B16F1 and Tib6 tumor models.[2]
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| Enzyme Assay |
In 96-well plates, A549 cells expressing endogenous human WT c-Met are plated in growth medium and allowed to grow for the entire night. The growth medium is switched out for serum-free medium (containing 0.04% BSA) on the second day of the experiment. Each well receives serial dilutions of PF-04217903, and the cells are incubated for an hour at 37 °C. The cells are then treated with 40 ng/mL of HGF for 20 minutes. After giving the cells one wash in HBSS supplemented with 1 mM Na3VO4, lysis buffer is used to extract the protein from the cells. An ELISA technique that uses capture antibodies specific to c-Met and a detection antibody specific to phosphorylated tyrosine residues is used to measure the phosphorylation of c-Met. Protein lysates are added to antibody-coated plates, which are then incubated at 4 °C for an entire night before being seven times cleaned with 1% Tween 20 in PBS. Each plate is treated with 1:500 diluted horseradish peroxidase-conjugated anti-phosphotyrosine (HRP-PY20) for 30 minutes. After another round of washing the plates, the HRP-dependent colorimetric reaction is started with the addition of TMB peroxidase substrate, and it is halted with the addition of 0.09 N H2SO4. Using a spectrophotometer, the absorbance at 450 nm is used to determine the ELISA end points. By fitting a concentration-response curve with a four-parameter analytical method based on Microsoft Excel, the IC50 value is determined.
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| Cell Assay |
For four days, cells are exposed to varying concentrations of PF-04217903. Using a Coulter counter machine to count the contents of each well, cell proliferation is evaluated.
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| Animal Protocol |
Immunodeficient nude mice (nu/nu) subcutaneously implanted with tumor cell lines B16F1, EL4, LLC, or Tib6
45 mg/kg Orally |
| References |
| Molecular Formula |
C19H16N8O
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|---|---|
| Molecular Weight |
372.38
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| Exact Mass |
372.14
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| Elemental Analysis |
C, 61.28; H, 4.33; N, 30.09; O, 4.30
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| CAS # |
956905-27-4
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| Related CAS # |
PF-04217903 mesylate;956906-93-7;PF-04217903 phenolsulfonate;1159490-85-3
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| Appearance |
white solid powder
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| SMILES |
C1=CC2=C(C=CC(=C2)CN3C4=NC(=CN=C4N=N3)C5=CN(N=C5)CCO)N=C1
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| InChi Key |
PDMUGYOXRHVNMO-UHFFFAOYSA-N
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| 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
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| Chemical Name |
2-[4-[3-(quinolin-6-ylmethyl)triazolo[4,5-b]pyrazin-5-yl]pyrazol-1-yl]ethanol
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| Synonyms |
PF04217903; PF4217903; PF-4217903; PF 04217903; PF-04217903; PF 4217903
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2 mg/mL (5.37 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2 mg/mL (5.37 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2 mg/mL (5.37 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 1% DMSO+30% polyethylene glycol+1% Tween 80: 30 mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6854 mL | 13.4271 mL | 26.8543 mL | |
| 5 mM | 0.5371 mL | 2.6854 mL | 5.3709 mL | |
| 10 mM | 0.2685 mL | 1.3427 mL | 2.6854 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00706355 | Terminated | Drug: PF-04217903 | Neoplasms | Pfizer | August 2008 | Phase 1 |
Endothelial cells, but not tumor cells, are mainly targeted by HGF/c-Met axis.Cancer Res.2010Dec 15;70(24):10090-100. |
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.Cancer Res.2010Dec 15;70(24):10090-100. |
Inhibition of angiogenesis is one of the mechanisms by which combination treatment affects tumor growth.Cancer Res.2010Dec 15;70(24):10090-100. |
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