1. Protein Tyrosine Kinase/RTK
    Protein Tyrosine Kinase/RTK
  2. VEGFR
    c-Met/HGFR

Foretinib (Synonyms: XL880; GSK1363089; GSK089; EXEL-2880)

Cat. No.: HY-10338 Purity: 99.81%
Data Sheet SDS Handling Instructions

Foretinib is an ATP-competitive inhibitor of HGFR and VEGFR, with IC50 of 0.4 nM and 0.9 nM for Met and KDR, less potent against Ron, Flt-1/3/4, Kit, PDGFRα/β and Tie-2, and has little activity to FGFR1 and EGFR.

For research use only. We do not sell to patients.
Foretinib Chemical Structure

Foretinib Chemical Structure

CAS No. : 849217-64-7

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10 mM * 1 mL in DMSO $70 In-stock
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10 mg $70 In-stock
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Description

Foretinib is an ATP-competitive inhibitor of HGFR and VEGFR, with IC50 of 0.4 nM and 0.9 nM for Met and KDR, less potent against Ron, Flt-1/3/4, Kit, PDGFRα/β and Tie-2, and has little activity to FGFR1 and EGFR.

IC50 & Target

IC50: 0.4 nM (Met), 0.9 nM (KDR)

In Vitro

Foretinib inhibits HGF receptor family tyrosine kinases with IC50 values of 0.4 nM for Met and 3 nM for Ron. Foretinib also inhibits KDR, Flt-1, and Flt-4 with IC50 values of 0.9 nM, 6.8 nM and 2.8 nM, respectively. Foretinib 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 Foretinib affects cell growth differently in gastric cancer cell lines MKN-45 and KATO-III. Foretinib inhibits phosphorylation of MET and downstream signaling molecules in MKN-45 cells, while targets GFGR2 in KATO-III cells[2].

In Vivo

Foretinib (100 mg/kg, p.o.) 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 persist through 24 hours. Foretinib (30-100 mg/kg, once daily, p.o.) 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 Foretinib, respectively. Foretinib 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 Foretinib is well tolerated with no significant body weight loss[1]. Foretinib is developed to target abnormal signaling of HGF through Met and simultaneously target several receptors tyrosine kinase involved in tumor angiogenesis. Foretinib causes 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].

Clinical Trial
NCT Number Sponsor Condition Start Date Phase
NCT00725764 GlaxoSmithKline Neoplasms, Head and Neck August 2007 Phase 2
NCT00742261 GlaxoSmithKline Solid Tumours August 2008 Phase 1
NCT00725712 GlaxoSmithKline Neoplasms, Gastrointestinal Tract March 2007 Phase 2
NCT00920192 GlaxoSmithKline Carcinoma, Hepatocellular August 12, 2009 Phase 1
NCT00726323 GlaxoSmithKline Carcinoma, Renal Cell June 2006 Phase 2
NCT00743067 GlaxoSmithKline Solid Tumours August 2006 Phase 1
NCT00742131 GlaxoSmithKline Solid Tumours March 2005 Phase 1
NCT01147484 NCIC Clinical Trials Group|Canadian Cancer Trials Group Recurrent Breast Cancer May 2010 Phase 2
NCT01138384 NCIC Clinical Trials Group|Canadian Cancer Trials Group Breast Cancer June 2010 Phase 1|Phase 2
NCT02034097 GlaxoSmithKline Cancer April 2014 Phase 2
NCT01068587 NCIC Clinical Trials Group|Canadian Cancer Trials Group Lung Cancer December 2009 Phase 1|Phase 2
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References
Preparing Stock Solutions
Concentration Volume (DMSO) Mass 1 mg 5 mg 10 mg
1 mM 1.5807 mL 7.9033 mL 15.8065 mL
5 mM 0.3161 mL 1.5807 mL 3.1613 mL
10 mM 0.1581 mL 0.7903 mL 1.5807 mL
Kinase Assay
[1]

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. 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 NaN3. 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. 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 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. 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.

Cell Assay
[1]

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.

Animal Administration
[1]

Foretinib is formulated in 0.9% normal saline.

In vivo target modulation studies are done in naive mice or mice bearing B16F10 tumors. Foretinib or vehicle (0.9% normal saline) is administered at 10 mL/kg via oral gavage. For examination of Met phosphorylation in liver, HGF (10 μg/mouse) is administered i.v. 10 min before harvest. For examination of Flk-1/KDR phosphorylation in lung, VEGF (10 μg/mouse) is administered i.v. 30 min before harvest 0.5 h later. Receptor phosphorylation analysis is determined by immunoblot analysis.

References
M.Wt

632.65

Formula

C₃₄H₃₄F₂N₄O₆

CAS No.

849217-64-7

Storage
Powder -20°C 3 years
  4°C 2 years
In solvent -80°C 6 months
  -20°C 1 month
Shipping

Room temperature in continental US; may vary elsewhere

Solvent & Solubility

DMSO: ≥ 38 mg/mL

* "<1 mg/mL" means slightly soluble or insoluble. "≥" means soluble, but saturation unknown.

Purity: 99.81%

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Foretinib
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