ホームページ Protein Tyrosine Kinase c-Met inhibitor - VEGFR inhibitor - FLT3 inhibitor - c-Kit inhibitor - PDGFR inhibitor Foretinib For research use only.

Foretinib

別名：GSK1363089, EXEL-2880, XL-880, GSK089

Foretinib is an ATP-competitive inhibitor of HGFR and VEGFR, mostly for Met (c-Met) and KDR with IC50 of 0.4 nM and 0.9 nM in cell-free assays. Less potent against Ron, Flt-1/3/4, Kit (c-Kit), PDGFRα/β and Tie-2, and little activity to FGFR1 and EGFR. Phase 2.

Foretinib化学構造

CAS No. 849217-64-7

サイズ 価格(税別) 在庫状況
10mM (1mL in DMSO) JPY 42900 国内在庫あり
JPY 25500 国内在庫あり
JPY 104500 国内在庫あり
JPY 448500 国内在庫なし(納期7~10日)

代表番号: 045-509-1970|電子メール：sales@selleck.co.jp
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製品安全説明書

現在のバッチを見る： S111106 DMSO] 100 mg/mL] false] Water] Insoluble] false] Ethanol] Insoluble] false 純度： 99.82%
99.82

Foretinib関連製品

シグナル伝達経路

c-Met Signaling Pathways

c-Metシグナル伝達経路

c-Met阻害剤の選択性比較

Cell Data

Cell Lines Assay Type Concentration Incubation Time 活性情報 PMID
U251 Function Assay 100/300/900 nM 24 h abrogates migration and invasion of glioma cells in a dose dependent manner 24658326
SF188 Function Assay 100/300/900 nM 24 h abrogates migration and invasion of glioma cells in a dose dependent manner 24658326
A172 Growth Inhibition Assay 100/300/900 nM 48 h reduces cell survival at 900 nM significantly 24658326
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生物活性

製品説明 Foretinib is an ATP-competitive inhibitor of HGFR and VEGFR, mostly for Met (c-Met) and KDR with IC50 of 0.4 nM and 0.9 nM in cell-free assays. Less potent against Ron, Flt-1/3/4, Kit (c-Kit), PDGFRα/β and Tie-2, and little activity to FGFR1 and EGFR. Phase 2.
Targets
Met [1]
(Cell-free assay)		 KDR [1]
(Cell-free assay)		 Tie-2 [1]
(Cell-free assay)		 VEGFR3/FLT4 [1]
(Cell-free assay)		 RON [1]
(Cell-free assay)		 もっとクリックする
0.4 nM 0.86 nM 1.1 nM 2.8 nM 3 nM
In Vitro
In vitro XL880 inhibits HGF receptor family tyrosine kinases with IC50 values of 0.4 nM for Met and 3 nM for Ron. XL880 also inhibits KDR, Flt-1, and Flt-4 with IC50 values of 0.9 nM, 6.8 nM and 2.8 nM, respectively. XL880 inhibits colony growth of B16F10, A549 and HT29 cells with IC50 of 40 nM, 29 nM and 165 nM, respectively. [1] A recent study indicates XL880 affects cell growth differently in gastric cancer cell lines MKN-45 and KATO-III. XL880 inhibits phosphorylation of MET and downstream signaling molecules in MKN-45 cells, while targets GFGR2 in KATO-III cells. [2]
Kinase Assay Kinase Inhibition Assay
Kinase inhibition is investigated using one of three assay formats: [33P]phosphoryl transfer, luciferase-coupled chemiluminescence, or AlphaScreen tyrosine kinase technology. IC50s are calculated by nonlinear regression analysis using XLFit.33P -Phosphoryl Transfer Kinase Assay Reactions are performed in 384-well white, clear bottom, high-binding microtiter plates (Greiner, Monroe, NC). Plates are coated with 2 μg/well of protein or peptide substrate in a 50 μL volume of coating buffer contained 40 μg/mL substrate (poly(Glu, Tyr) 4:1, 22.5 mM Na2CO3, 27.5 mM NaHCO3, 50 mM NaCl and 3 mM NaN 3. Coated plates are washed once with 50 μL of assay buffer following overnight incubation at room temperature (RT). Test compounds and enzymes are combined with 33P-γ-ATP (3.3 μCi/nmol) in a total volume of 20 μL. The reaction mixture is incubated at RT for 2 hours and terminated by aspiration. The microtiter plates are subsequently washed 6 times with 0.05% Tween-PBS buffer (PBST). Scintillation fluid (50 μL/well) is added and incorporated 33P is measured by liquid scintillation spectrometry using a MicroBeta scintillation counter.Luciferase-Coupled Chemiluminescence Assay Reactions are conducted in 384-well white, medium binding microtiter plates (Greiner). In a first step enzyme and compound are combined and incubated for 60 minutes; reactions are initiated by addition of ATP and peptide substrate (poly(Glu, Tyr) 4:1) in a final voume of 20 μL, and incubated at RT for 2-4 hours. Following the kinase reaction, a 20 μL aliquot of Kinase Glo (Promega, Madison, WI) is added and luminescence signal is measured using a Victor plate reader. Total ATP consumption is limited to 50%. AlphaScreenTM Tyrosine Kinase Assay Donor beads coated with streptavidin and acceptor beads coated with PY100 anti-phosphotyrosine antibody are used. Biotinylated poly(Glu,Tyr) 4:1 is used as the substrate. Substrate phosphorylation is measured by addition of donor/acceptor beads by luminescence following donor-acceptor bead complex formation. Kinase and test compounds are combined and preincubated for 60 minutes, followed by addition of ATP, and biotinylated poly(Glu, Tyr) in a total volume of 20 μL in 384-well white, medium binding microtiter plates (Greiner). Reaction mixtures are incubated for 1 hour at room temperature. Reactions are quenched by addition of 10 μL of 15-30 μg/mL AlphaScreen bead suspension containing 75 mM Hepes, pH 7.4, 300 mM NaCl, 120 mM EDTA, 0.3% BSA and 0.03% Tween-20. After 2-16 hours incubation at room temperature plates are read using an AlphaQuest reader.
細胞実験 細胞株 B16F10, A549, and HT29 cells
濃度 40 nM
反応時間 12 to 14 days
実験の流れ

B16F10, A549, and HT29 cells (1.2× 103 per well) are mixed with soft agar and seeded in a 96-well plate containing 10% FBS and EXEL-2880 over a base agar layer. For normoxic conditions, the plates are incubated (37°C) for 12 to 14 days in 21% oxygen, 5% CO2, and 74% nitrogen, whereas incubation (37 °C) under hypoxic conditions is done in a hypoxia chamber in 1% oxygen, 5% CO2, and 94% nitrogen. The number of colonies is evaluated under each condition following addition of 50% Alamar Blue and fluorescence detection.
実験結果図 Methods Biomarkers 結果図 PMID
Western blot p-Met / Met / p-Akt / Akt p-MDM2 / p53 / PUMA pROS1 / tROS1 / pSHP2 / pERK / ERK 29854314
Growth inhibition assay Cell viability 29854314
In Vivo
In Vivo A single 100 mg/kg oral gavage dose of XL880 results in substantial inhibition of phosphorylation of B16F10 tumor Met and ligand (e.g., HGFor VEGF)-induced receptor phosphorylation of Met in liver and Flk-1/KDR in lung, which both persisted through 24 hours. Treatment with XL880 (30-100 mg/kg, once daily, oral gavage) results in reduction in tumor burden. The lung surface tumor burden is reduced by 50% and 58% following treatment with 30 and 100 mg/kg XL880, respectively. XL880 treatment of mice bearing B16F10 solid tumors also results in dose-dependent tumor growth inhibition of 64% and 87% at 30 and 100 mg/kg, respectively. For both studies, administration of XL880 is well tolerated with no significant body weight loss. [1] XL880 is developed to target abnormal signaling of HGF through Met and simultaneously target several receptors tyrosine kinase involved in tumor angiogenesis. XL880 caused tumor hemorrhage and necrosis in human xenografts within 2 to 4 hours, and maximal tumornecrosis is observed at 96 hours (after five daily doses), resulting in complete regression. [3]
動物実験 動物モデル B16F10 tumor cells (2 × 10 5) are implanted via i.v. tail vein injection into athymic nude mice (NCr or BALB/c) 5 to 8 weeks old
投与量 100 mg/kg
投与経路 Administered via oral gavage
NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT00920192 Completed
Carcinoma Hepatocellular
GlaxoSmithKline
 August 12 2009 Phase 1
NCT00742261 Completed
Solid Tumours
GlaxoSmithKline
 August 11 2008 Phase 1
NCT00725764 Completed
Neoplasms Head and Neck
GlaxoSmithKline
 August 27 2007 Phase 2
NCT00725712 Completed
Neoplasms Gastrointestinal Tract
GlaxoSmithKline
 March 31 2007 Phase 2
NCT00743067 Completed
Solid Tumours
GlaxoSmithKline
 August 9 2006 Phase 1

化学情報

分子量 632.65 化学式

C34H34F2N4O6
CAS No. 849217-64-7 SDF Download Foretinib SDFをダウンロードする
Smiles COC1=CC2=C(C=CN=C2C=C1OCCCN3CCOCC3)OC4=C(C=C(C=C4)NC(=O)C5(CC5)C(=O)NC6=CC=C(C=C6)F)F
保管

In vitro
Batch:

DMSO : 100 mg/mL ( (158.06 mM)； 吸湿したDMSOは溶解度を減少させます。新しいDMSOをご使用ください。)

Water : Insoluble

Ethanol : Insoluble

モル濃度計算器

in vivo
Batch:

Add solvents to the product individually and in order.

投与溶液組成計算機
Clear solution
30%propylene glycol 5% 65%D5W
30.0mg/ml (47.42mM) Taking the 1 mL working solution as an example, add 300 μL of 100 mg/ml clarified propylene glycol stock solution to 50 μL of Tween 80, mix evenly to clarify it; then continue to add 650 μL of D5W to adjust the volume to 1 mL. The mixed solution should be used immediately for optimal results. 

実験計算

モル濃度計算器

質量 濃度 体積 分子量

投与溶液組成計算機(クリア溶液)

ステップ１：実験データを入力してください。（実験操作によるロスを考慮し、動物数を1匹分多くして計算・調製することを推奨します）

mg/kg g μL 匹

ステップ２：投与溶媒の組成を入力してください。（ロット毎に適した溶解組成が異なる場合があります。詳細については弊社までお問い合わせください）

% DMSO % % Tween 80 % ddH2O
%DMSO %

計算結果：

投与溶媒濃度： mg/ml;

DMSOストック溶液調製方法： mg 試薬を μL DMSOに溶解する（濃度 mg/mL, 注：濃度が当該ロットのDMSO溶解度を超える場合はご連絡ください。 )

投与溶媒調製方法：Take μL DMSOストック溶液に μL PEG300，を加え、完全溶解後μL Tween 80，を加えて完全溶解させた後 μL ddH2O，を加え完全に溶解させます。

投与溶媒調製方法：μL DMSOストック溶液に μL Corn oil，を加え、完全溶解。

注意：１.ストック溶液に沈殿、混濁などがないことをご確認ください；
２.順番通りに溶剤を加えてください。次のステップに進む前に溶液に沈殿、混濁などがないことを確認してから加えてください。ボルテックス、ソニケーション、水浴加熱など物理的な方法で溶解を早めることは可能です。

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