PF-04217903

製品コードS1094 バッチS109406

印刷

化学情報

Chemical Structure Synonyms N/A Storage
(From the date of receipt)		 3 years -20°C powder
1 years -80°C in solvent
化学式

C19H16N8O
分子量 372.38 CAS No. 956905-27-4
Solubility (25°C)* 体外 DMSO 74 mg/mL (198.72 mM)
Water Insoluble
Ethanol Insoluble
* <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.

溶剤液（一定の濃度）を調合する

生物活性

製品説明 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.
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]

プロトコル(参考用のみ)

キナーゼアッセイ 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 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 動物モデル Immunodeficient nude mice (nu/nu) subcutaneously implanted with tumor cell lines B16F1, EL4, LLC, or Tib6
投薬量 45 mg/kg
投与方法 Orally

カスタマーフィードバック

Data from [Data independently produced by Eur J Cancer, 2011, 47(8), 1231-43]

Data independently produced by , , Dr. Zhang of Tianjin Medical University

Data from [Data independently produced by , , J Clin Invest, 2016, 126(6):2181-90]

Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：

Divergent Polypharmacology-Driven Cellular Activity of Structurally Similar Multi-Kinase Inhibitors through Cumulative Effects on Individual Targets [ Cell Chem Biol, 2019, 10.1016/j.chembiol.2019.06.003] PubMed: 31257184
Liver X Receptor Agonism Sensitizes a Subset of Hepatocellular Carcinoma to Sorafenib by Dual-Inhibiting MET and EGFR. [ Neoplasia, 2019, 22(1):1-9] PubMed: 31751859
Off-target based drug repurposing opportunities for tivantinib in acute myeloid leukemia [ Sci Rep, 2019, 9(1):606] PubMed: 30679640
DRUGPATH - a novel bioinformatic approach identifies DNA-damage pathway as a regulator of size maintenance in human ESCs and iPSCs [ Sci Rep, 2019, 9(1):1897] PubMed: 30760778
Hgf/Met activation mediates resistance to BRAF inhibition in murine anaplastic thyroid cancers. [ J Clin Invest, 2018, 128(9):4086-4097] PubMed: 29990309
The dual blockade of MET and VEGFR2 signaling demonstrates pronounced inhibition on tumor growth and metastasis of hepatocellular carcinoma [Zhang Y, et al. J Exp Clin Cancer Res, 2018, 37(1):93] PubMed: 29712569
MET-targeting antibody (emibetuzumab) and kinase inhibitor (merestinib) as single agent or in combination in a cancer model bearing MET exon 14 skipping. [ Invest New Drugs, 2018, 36(4):536-544] PubMed: 29188469
Reactive Neutrophil Responses Dependent on the Receptor Tyrosine Kinase c-MET Limit Cancer Immunotherapy. [ Immunity, 2017, 47(4):789-802] PubMed: 29045907
Cabozantinib Eradicates Advanced Murine Prostate Cancer by Activating Antitumor Innate Immunity. [ Cancer Discov, 2017, 7(7):750-765] PubMed: 28274958
Cotargeting MNK and MEK kinases induces the regression ofNF1-mutant cancers [ J Clin Invest., 2016, 126(6):2181-2190] PubMed: None

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人間や獣医の診断であるか治療的な使用のためにでない。

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