Foretinib (GSK1363089)

Catalog No.S1111 Synonyms: EXEL-2880,XL-880

Foretinib (GSK1363089) Chemical Structure

Molecular Weight(MW): 632.65

Foretinib (GSK1363089) is an ATP-competitive inhibitor of HGFR and VEGFR, mostly for 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, PDGFRα/β and Tie-2, and little activity to FGFR1 and EGFR. Phase 2.

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Cited by 23 Publications

Purity & Quality Control

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Biological Activity

Description Foretinib (GSK1363089) is an ATP-competitive inhibitor of HGFR and VEGFR, mostly for 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, 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)
0.4 nM 0.86 nM 1.1 nM 2.8 nM 3 nM
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]

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
Daoy  MYXGeY5kfGmxbjDBd5NigQ>? MX[wMlUwOS9{LkWg{txO NUHwPGJYOjRiaB?= MnHISG1UVw>? MV\pcohq[mm2czD0bIUhUEeILXnu[JVk\WRiY13FWEBx[XSqd3H5JIFkfGm4YYTpc44> MYCyOVM6OTJ2MR?=
ONS76 Ml3ZSpVv[3Srb36gRZN{[Xl? M1eyWFAvPS9zL{KuOUDPxE1? M{nQOlI1KGh? NGPBOVFFVVOR MULpcohq[mm2czD0bIUhUEeILXnu[JVk\WRiY13FWEBx[XSqd3H5JIFkfGm4YYTpc44> NEHYWVYzPTN7MUK0NS=>
Daoy  M1rldGZ2dmO2aX;uJGF{e2G7 NV\qeFhxOC53L{GvNk42KM7:TR?= Mn\ENlQhcA>? M1HRTGROW09? NILQTmZqdmirYnn0d{BJT0ZvbXXkbYF1\WRibXnndoF1cW:wIHHu[EBqdn[jc3nvci=> M3fJclI2OzlzMkSx
ONS76 NYTqfnBCTnWwY4Tpc44hSXO|YYm= Mkm3NE42NzFxMj61JO69VQ>? MViyOEBp MWXEUXNQ M4faWYlvcGmkaYTzJGhITi2vZXTpZZRm\CCvaXfyZZRqd25iYX7kJIlvfmG|aX;u MVKyOVM6OTJ2MR?=
Daoy  NV;K[ZFpSXCxcITvd4l{KEG|c3H5 NFnae2EyKM7:TR?= MYSyOEBp NIHXeG9FVVOR NVjveWUxcW6mdXPld{BieG:ydH;zbZM> NVvPcoNyOjV|OUGyOFE>
Daoy  M1jhUGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NID5bWwxNjVxMT:yMlUh|ryP NWrmZVQzOjRvOU[gbC=> NIDjdJJFVVOR NWizXGtQcW6qaXLpeJMh[2WubDDndo94fGhiaX6gZUBld3OnIHTldIVv\GWwdDDtZY5v\XJ? NHPJNFEzPTN7MUK0NS=>
U251 M1XNUWZ2dmO2aX;uJGF{e2G7 NFnnO5IyODBxM{CwM|kxOCCwTR?= MnjSNUBp M1y0b2ROW09? NHP1[XZqdmirYnn0d{B1cGVicHjvd5Bpd3K7bHH0bY9vKG:oIF3ldnRMyqB? NVroVWlDOjR4NUizNlY>
A172 MYfGeY5kfGmxbjDBd5NigQ>? NFHzOmIyODBxM{CwM|kxOCCwTR?= MkS4NUBp MUPEUXNQ NET5cXlqdmirYnn0d{B1cGVicHjvd5Bpd3K7bHH0bY9vKG:oIF3ldnRMyqB? MUeyOFY2QDN{Nh?=
SF188 MWPGeY5kfGmxbjDBd5NigQ>? MV:xNFAwOzByL{mwNEBvVQ>? NUDPV4JYOSCq MmnqSG1UVw>? NXr4[m5ucW6qaXLpeJMhfGinIIDoc5NxcG:{eXzheIlwdiCxZjDN[ZJVU8Li NYrQVpRGOjR4NUizNlY>
U251 NWHqZmo3TnWwY4Tpc44hSXO|YYm= NIHaT4YyODBxM{CwM|kxOCCwTR?= M2XBXVEhcA>? NVfSOJBiTE2VTx?= MnLQbY5pcWKrdIOgeIhmKGGldHn2bZR6KG:oIFH4cEwhXHm{b{O= M4nycFI1PjV6M{K2
A172 M3zj[WZ2dmO2aX;uJGF{e2G7 MmnLNVAxNzNyMD:5NFAhdk1? MY[xJIg> MXnEUXNQ NXe1OHFFcW6qaXLpeJMhfGinIHHjeIl3cXS7IH;mJGF5dCxiVInyc|M> NFLlc2ozPDZ3OEOyOi=>
SF188 NWHrbmxuTnWwY4Tpc44hSXO|YYm= NYSzRWlWOTByL{OwNE86ODBibl2= M2n3eVEhcA>? NI\GS2dFVVOR NWm1[m5vcW6qaXLpeJMhfGinIHHjeIl3cXS7IH;mJGF5dCxiVInyc|M> NWL6[FFoOjR4NUizNlY>
U251 NXLLWFA2TnWwY4Tpc44hSXO|YYm= MX2xNFAwOzByL{mwNEBvVQ>? MlqxNUBp MYDEUXNQ NXT1VWtV\GWlcnXhd4V{KEGtdDDwbI9{eGixconsZZRqd25iaX6gZUBkd26lZX70doF1cW:wIHTldIVv\GWwdDDtZY5v\XJ? M3XXT|I1PjV6M{K2
A172 NXTtWYFNTnWwY4Tpc44hSXO|YYm= MXixNFAwOzByL{mwNEBvVQ>? NXvtOZJjOSCq MkfzSG1UVw>? NYfNVlFv\GWlcnXhd4V{KEGtdDDwbI9{eGixconsZZRqd25iaX6gZUBkd26lZX70doF1cW:wIHTldIVv\GWwdDDtZY5v\XJ? MViyOFY2QDN{Nh?=
SF188 NVzRSW8zTnWwY4Tpc44hSXO|YYm= MkHuNVAxNzNyMD:5NFAhdk1? MVOxJIg> NYfXPFB6TE2VTx?= Mlm0[IVkemWjc3XzJGFsfCCyaH;zdIhwenmuYYTpc44hcW5iYTDjc45k\W62cnH0bY9vKGSncHXu[IVvfCCvYX7u[ZI> NX;iU245OjR4NUizNlY>
U251 NF;uSnJHfW6ldHnvckBCe3OjeR?= MmPoNVAxNzNyMD:5NFAhdk1? M17uTlI5KGh? NFvmXlBFVVOR MXjpcoR2[2W|IGDBVnAh[2ynYY\h[4U> MUmyOFY2QDN{Nh?=
SF188 MofDSpVv[3Srb36gRZN{[Xl? MkHsNVAxNzNyMD:5NFAhdk1? MX:yPEBp NIPBZpJFVVOR NXTvb3p4cW6mdXPld{BRSVKSIHPs[YF3[Wen NUTNSFM1OjR4NUizNlY>
SF188 MnrCS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M{fTRVExOC9|MECvPVAxKG6P NUjxV5pPPDhiaB?= NW\RbYRZTE2VTx?= MYjy[YR2[2W|IHPlcIwhe3W{dnn2ZYwh[XRiOUCwJI5OKHOrZ37p[olk[W62bIm= MlPRNlQ3PTh|Mk[=
U251 NX\hemNrT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NG\nb48yODBxM{CwM|kxOCCwTR?= NWO3Z4hLPDhiaB?= MkC2SG1UVw>? M1i1b5Jm\HWlZYOgZ4VtdCC|dYL2bZZidCCjdDC5NFAhdk1ic3nncolncWOjboTsfS=> MX[yOFY2QDN{Nh?=
A172 M1jsV2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MorpNVAxNzNyMD:5NFAhdk1? NFrWSYw1QCCq MU\EUXNQ NXzGbHcxemWmdXPld{Bk\WyuIIP1dpZqfmGuIHH0JFkxOCCwTTDzbYdvcW[rY3HueIx6 Mn7yNlQ3PTh|Mk[=
SF188 Ml73SpVv[3Srb36gRZN{[Xl? NX;x[HBzOTByL{OwNE86ODBibl2= NEfCR2YzPCCq Mnq4SG1UVw>? MX;hZpJw\2G2ZYOgcYloemG2aX;uJIFv\CCrbo\hd4lwdiCxZjDncIlwdWFiY3XscJMhcW5iYTDkc5NmKGSncHXu[IVvfCCvYX7u[ZI> MYCyOFY2QDN{Nh?=
U251 MlGxSpVv[3Srb36gRZN{[Xl? NUKzfIl2OTByL{OwNE86ODBibl2= MmDpNlQhcA>? MmHmSG1UVw>? NV21RXds[WK{b3fheIV{KG2rZ4LheIlwdiCjbnSgbY53[XOrb36gc4Yh\2yrb33hJINmdGy|IHnuJIEh\G:|ZTDk[ZBmdmSnboSgcYFvdmW{ MWiyOFY2QDN{Nh?=
A172 NXXGbXZsTnWwY4Tpc44hSXO|YYm= NXS5bJRIOTByL{OwNE86ODBibl2= NHq4WXczPCCq MUHEUXNQ M4GyR4Fjem:pYYTld{BucWe{YYTpc44h[W6mIHnueoF{cW:wIH;mJIdtcW:vYTDj[YxteyCrbjDhJIRwe2ViZHXw[Y5l\W62IH3hco5meg>? MnPZNlQ3PTh|Mk[=
Ba/F3 NVWzeXoxS2WubDDWbYFjcWyrdImgRZN{[Xl? NGLRSWExNjByMEGtNVAh|ryP NF\Pdnc4OiCq MV\pcohq[mm2czDj[YxtKGe{b4f0bEBqdiCjIHTvd4Uh\GWyZX7k[Y51KG2jbn7ldi=> NUKwc|BHOjR{MUi1PFk>
HCC78 NIj5WWpE\WyuIG\pZYJqdGm2eTDBd5NigQ>? M{DtXVAvODFvMUCg{txO MnLtO|IhcA>? M33XT4lvcGmkaYTzJINmdGxiZ4Lve5RpKGmwIHGg[I9{\SCmZYDlcoRmdnRibXHucoVz MUKyOFIyQDV6OR?=
SK-HEP1 NYrnWGhLS2WubDDWbYFjcWyrdImgRZN{[Xl? MlTRNE4zPS1zLkWg{txO NUXpPJJiOjUEoHi= M1fPW4lvcGmkaYTzJINmdGxiZ4Lve5RpKGmwIHGg[I9{\SCmZYDlcoRmdnRibXHucoVz NVfEPYdIOjJzOEexO|E>
SK-HEP2 M{PycWZ2dmO2aX;uJGF{e2G7 MX:xJO69VQ>? NXS0bo9NOjRiaB?= NXu3eZpx[myxY3vzJGhITi2rbnT1Z4VlKGOnbHygcY91cWyrdIm= NWixVGpCOjJzOEexO|E>
SK-HEP2 NW\2TmdjTnWwY4Tpc44hSXO|YYm= MXexJO69VQ>? MorZNlQhcA>? M3XES4NifXOnczDHNk9OKHCqYYPlJIFzemW|dDD3bZRpKHKnZIXjeIlwdiCrbjD0bIUhTzBxR{JCpIFv\CCVIIDoZZNmew>? MomzNlIyQDdzN{G=
MKN-45  NUi1OWdbT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NXnINWU1OC5yMT2xNEDPxE1? NYfYXohoPSCm MUPJR|UxRThibl2= MnXtNlE3PTV7MUi=
KATO-III MVfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? Mn:yNE4xOS1zMDFOwG0> M173U|Uh\A>? NVTUfVBUUUN3ME2zNEBvVQ>? NF\y[WIzOTZ3NUmxPC=>
MKN-45  MYDGeY5kfGmxbjDBd5NigQ>? NEnqO|IyKM7:TR?= M{fjRlI1KGh? Mo\EbY5pcWKrdIOgdIhwe3Cqb4L5cIF1cW:wIH;mJG1GXCxiQXv0MEBidmRiRWLLNU8zKGmwIF3LUk01PQ>? NVKxTnlFOjF4NUW5NVg>
KATO-III NE\IdIZHfW6ldHnvckBCe3OjeR?= M1HZRVEh|ryP M{\Nd|I1KGh? NFzaSIpqdmirYnn0d{BxcG:|cHjvdplt[XSrb36gc4YhVUWWLDDBb5QtKGGwZDDFVmsyNzJiaX6gUWtPNTR3 Mn3NNlE3PTV7MUi=
H1648 MoTBS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MVvJR|UxRTFwMkigxtExNjF{IN88US=> NXj0bZZQOjF{NUKyPFQ>
H1573 MX\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M{HGTWlEPTB;MT62NkDDuSByLkC1JO69VQ>? M3TSWVIyOjV{Mki0
H596 MYTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MWnJR|UxRTFwMkGgxtEhOC5zNzFOwG0> MniwNlEzPTJ{OES=
HOP92 MWXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MVHJR|UxRTBwOEGgxtEhOC5{OTFOwG0> M1:1c|IyOjV{Mki0
H69 MXjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MkDOTWM2OD1zLkG4JOKyKDBwMEig{txO MWeyNVI2OjJ6NB?=
H1975 MWrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MlW2TWM2OD1zLkO5JOKyKDBwM{Og{txO NVzQeJlIOjF{NUKyPFQ>
SCC15 MYHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NWfLeIhKUUN3ME2wMlY{KMLzIECuNFQh|ryP M{TOZ|IyOjV{Mki0
HN5 MoW0S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NYmxPYZYUUN3ME2wMlY2KMLzIECuNlYh|ryP MW[yNVI2OjJ6NB?=

... Click to View More Cell Line Experimental Data

Assay
Methods Test Index PMID
Western blot
p-Met / Met / p-Akt / Akt ; 

PubMed: 29854314     


After serum starvation, the cells were treated with vehicle or foretinib for 24 hours. The cell lysates were analyzed by Western blotting using antibodies against p-Met, Met, p-Akt and Akt. Representative examples of bands from Western blots

p-MDM2 / p53 / PUMA ; 

PubMed: 29854314     


After serum starvation, the cells were treated with vehicle or foretinib for 24 hours. The cell lysates were analyzed by Western blotting using antibodies against p-MDM2, p53, PUMA and ACTB. 

pROS1 / tROS1 / pSHP2 / pERK / ERK ; 

PubMed: 24218589     


Immunoblot analysis of FIG-ROS fusion protein phosphorylation and downstream effector modulation after varying doses of crizotinib and foretinib. Cropped images representative of three independent experiments are shown.

29854314 24218589
Growth inhibition assay
Cell viability ; 

PubMed: 29854314     


EC cells were treated with various concentrations of foretinib for 48 hours and then their proliferation was measured by an MTS assay. 

29854314
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]

Protocol

Kinase Assay:

[1]

+ Expand

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.
Cell Research:

[1]

+ Expand
  • Cell lines: B16F10, A549, and HT29 cells
  • Concentrations: 40 nM
  • Incubation Time: 12 to 14 days
  • Method:

    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.


    (Only for Reference)
Animal Research:

[1]

+ Expand
  • Animal Models: 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
  • Formulation: 0.9% normal saline
  • Dosages: 100 mg/kg
  • Administration: Administered via oral gavage
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 100 mg/mL (158.06 mM)
Water Insoluble
Ethanol Insoluble
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
30% propylene glycol, 5% Tween 80, 65% D5W
For best results, use promptly after mixing.
30 mg/mL

* 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.

Chemical Information

Molecular Weight 632.65
Formula

C34H34F2N4O6

CAS No. 849217-64-7
Storage powder
in solvent
Synonyms EXEL-2880,XL-880

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Clinical Trial Information

NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT00920192 Completed Drug: Foretinib Carcinoma Hepatocellular GlaxoSmithKline August 12 2009 Phase 1
NCT00742261 Completed Drug: GSK1363089 Solid Tumours GlaxoSmithKline August 11 2008 Phase 1
NCT00725764 Completed Drug: GSK1363089 (foretinib) Neoplasms Head and Neck GlaxoSmithKline August 27 2007 Phase 2
NCT00725712 Completed Drug: GSK1363089 (formerly XL880) Neoplasms Gastrointestinal Tract GlaxoSmithKline March 31 2007 Phase 2
NCT00743067 Completed Drug: GSK1363089 (formerly XL880) Solid Tumours GlaxoSmithKline August 9 2006 Phase 1

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID