PF-04217903

PF-04217903は一種の選択性的で、ATP競争性的なc-Met阻害剤で、A549細胞の中にIC50値が4.8 nMです。PF-04217903は発癌性の突然変異型に敏感です(Y1230C突然変異型に敏感ではない)。臨床1期。

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PF-04217903 化学構造
分子量: 372.38

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製品説明

  • Compare c-Met Inhibitors
    c-Met製品生物活性の比較
  • 研究分野
  • PF-04217903のメカニズム

製品の説明

生物活性

製品説明 PF-04217903は一種の選択性的で、ATP競争性的なc-Met阻害剤で、A549細胞の中にIC50値が4.8 nMです。PF-04217903は発癌性の突然変異型に敏感です(Y1230C突然変異型に敏感ではない)。臨床1期。
ターゲット c-Met
IC50 4.8 nM [1]
In vitro試験 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試験 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]
臨床試験 A Phase I study to evaluate the effect of PF-04217903 in patients with advanced cancer has been terminated.
特集

プロトコル (参考用のみ)

キナーゼアッセイ: [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

細胞アッセイ: [2]

細胞株 B16F1, Tib6, EL4, and LLC, HUVECs and C166 cells
濃度 Dissolved in DMSO, final concentrations ~2 μM
反応時間 4 days
実験の流れ 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.

動物実験: [2]

動物モデル Immunodeficient nude mice (nu/nu) subcutaneously implanted with tumor cell lines B16F1, EL4, LLC, or Tib6
製剤 Dissolved in DMSO, and diluted in saline
投薬量 45 mg/kg
投与方法 Orally

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

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
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

参考

化学情報

Download PF-04217903 SDF
分子量 372.38
化学式

C19H16N8O

CAS No. 956905-27-4
保管 3年-20℃
2年-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 5 mg/mL (13.42 mM)
Water <1 mg/mL
Ethanol <1 mg/mL
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.
化学名 2-(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)-1H-pyrazol-1-yl)ethanol

文献中の引用 (6)

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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