WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 201372
CAS#: 849217-64-7 (free base)
Description: Foretinib, also known as XL880 and GSK1363089, is an orally bioavailable small molecule with potential antineoplastic activity. MET/VEGFR2 inhibitor GSK1363089 binds to and selectively inhibits hepatocyte growth factor (HGF) receptor c-MET and vascular endothelial growth factor receptor 2 (VEGFR2), which may result in the inhibition of tumor angiogenesis, tumor cell proliferation and metastasis. The proto-oncogene c-MET has been found to be over-expressed in a variety of cancers.
MedKoo Cat#: 201372
Name: Foretinib
CAS#: 849217-64-7 (free base)
Chemical Formula: C34H34F2N4O6
Exact Mass: 632.24464
Molecular Weight: 632.65
Elemental Analysis: C, 64.55; H, 5.42; F, 6.01; N, 8.86; O, 15.17
Related CAS #: 1226999-07-0 (phosphate) 849217-64-7 (free base)
Synonym: XL880; XL 880; XL-880; GSK1363089; GSK 1363089; GSK-1363089; GSK089; EXEL2880; Foretinib.
IUPAC/Chemical Name: N-[3-fluoro-4-({6-methoxy-7-[3-(morpholin-4-yl)propoxy]quinolin-4-yl}oxy)phenyl]-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
InChi Key: CXQHYVUVSFXTMY-UHFFFAOYSA-N
InChi Code: InChI=1S/C34H34F2N4O6/c1-43-30-20-25-27(21-31(30)45-16-2-13-40-14-17-44-18-15-40)37-12-9-28(25)46-29-8-7-24(19-26(29)36)39-33(42)34(10-11-34)32(41)38-23-5-3-22(35)4-6-23/h3-9,12,19-21H,2,10-11,13-18H2,1H3,(H,38,41)(H,39,42)
SMILES Code: O=C(C1(C(NC2=CC=C(F)C=C2)=O)CC1)NC3=CC=C(OC4=CC=NC5=CC(OCCCN6CCOCC6)=C(OC)C=C45)C(F)=C3
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
| Biological target: | Foretinib is a multi-target tyrosine kinase inhibitor with IC50s of 0.4 nM and 0.9 nM for Met and KDR. |
| In vitro activity: | EXEL-2880 is a potent inhibitor of cellular Met with IC50 values of 23 and 21 nmol/L, respectively, in PC-3 prostate cells and murine B16F10 melanoma cells. To further delineate the cellular effect of EXEL-2880, VEGF-induced extracellular signal-regulated kinase phosphorylation was used to assess the effect of the compound on phosphorylation of KDR in human umbilical vein endothelial cells that resulted in an IC50 of 16 nmol/L. The ability of EXEL-2880 to inhibit HGF-stimulated migration and invasion was tested using in vitro assays. Murine B16F10 melanoma cells express high levels of Met, which becomes highly phosphorylated when the cells are treated with HGF (Fig. 3A). B16F10 cells plated in the top well of a Transwell chamber containing a barrier with 0.8 μm pores show very little ability to migrate to the bottom chamber. Addition of HGF to the bottom chamber greatly increased migration through the barrier over a 24 h period, which was blocked by EXEL-2880 with an IC50 value of 44 nmol/L (Fig. 3C). Addition of HGF to the bottom chamber again produced a large increase in the number of cells migrating through a Matrigel barrier in response to HGF, and EXEL-2880 inhibited this effect with an IC50 value of 25 nmol/L ( Fig. 3D). Reference: Cancer Res. 2009 Oct 15;69(20):8009-16. http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=19808973 |
| In vivo activity: | A single 100 mg/kg oral gavage dose of EXEL-2880 resulted in substantial inhibition of phosphorylation of B16F10 tumor Met, which persisted through 24 h (Fig. 5A). In separate experiments, a single oral dose of EXEL-2880 inhibited ligand (e.g., HGF or VEGF)–induced receptor phosphorylation of Met in liver and Flk-1/KDR in lung through 24 h. The potent and long-lasting pharmacodynamic activity of EXEL-2880 in B16F10 solid tumors prompted efficacy studies in this same model although under different experimental conditions. As shown in Fig. 5B, i.v. implantation of B16F10 cells leads to accumulation of tumor cells in the lung where they implant and grow as malignant nodules resembling a model of lung metastasis. Once daily oral gavage administration of EXEL-2880 resulted in a dose-dependent reduction in tumor burden of 31% and 62%, respectively, for doses of 30 and 100 mg/kg as determined by a reduction in lung wet weights ( Fig. 5B). This reduction in lung wet weight was consistent with reductions in both the average size and the number of surface nodules in the lung. The lung surface tumor burden, calculated by multiplying the total nodule count by the average nodule diameter for each tumor, was reduced by 50% and 58% following treatment with 30 and 100 mg/kg EXEL-2880, respectively. In contrast, animals in the vehicle-treated control group exhibited a significant 2-fold increase in lung wet weight compared with animals treated with mock implantation (Supplementary Table S4). In a similar manner, EXEL-2880 treatment of mice bearing B16F10 solid tumors also resulted in dose-dependent tumor growth inhibition of 64% and 87% at 30 and 100 mg/kg, respectively (Supplementary Fig. S3). For both studies, administration of EXEL-2880 was well tolerated with no significant body weight loss. Reference: Cancer Res. 2009 Oct 15;69(20):8009-16. http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=19808973 |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 16.0 | 23.7 | |
| Ethanol | 25.0 | 39.5 |
The following data is based on the product molecular weight 632.65 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| In vitro protocol: | 1. Qian F, Engst S, Yamaguchi K, Yu P, Won KA, Mock L, Lou T, Tan J, Li C, Tam D, Lougheed J, Yakes FM, Bentzien F, Xu W, Zaks T, Wooster R, Greshock J, Joly AH. Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases. Cancer Res. 2009 Oct 15;69(20):8009-16. doi: 10.1158/0008-5472.CAN-08-4889. Epub 2009 Oct 6. PMID: 19808973. 2. Kataoka Y, Mukohara T, Tomioka H, Funakoshi Y, Kiyota N, Fujiwara Y, Yashiro M, Hirakawa K, Hirai M, Minami H. Foretinib (GSK1363089), a multi-kinase inhibitor of MET and VEGFRs, inhibits growth of gastric cancer cell lines by blocking inter-receptor tyrosine kinase networks. Invest New Drugs. 2012 Aug;30(4):1352-60. doi: 10.1007/s10637-011-9699-0. Epub 2011 Jun 8. PMID: 21655918. |
| In vivo protocol: | 1. Qian F, Engst S, Yamaguchi K, Yu P, Won KA, Mock L, Lou T, Tan J, Li C, Tam D, Lougheed J, Yakes FM, Bentzien F, Xu W, Zaks T, Wooster R, Greshock J, Joly AH. Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases. Cancer Res. 2009 Oct 15;69(20):8009-16. doi: 10.1158/0008-5472.CAN-08-4889. Epub 2009 Oct 6. PMID: 19808973. |
1: Bénard J. [ROS1 fusion proteins, targets of foretinib]. Bull Cancer. 2014 Jan 1;101(1):4. French. PubMed PMID: 24649496.
2: Davare MA, Saborowski A, Eide CA, Tognon C, Smith RL, Elferich J, Agarwal A, Tyner JW, Shinde UP, Lowe SW, Druker BJ. Foretinib is a potent inhibitor of oncogenic ROS1 fusion proteins. Proc Natl Acad Sci U S A. 2013 Nov 26;110(48):19519-24. doi: 10.1073/pnas.1319583110. Epub 2013 Nov 11. PubMed PMID: 24218589; PubMed Central PMCID: PMC3845150.
3: Shah MA, Wainberg ZA, Catenacci DV, Hochster HS, Ford J, Kunz P, Lee FC, Kallender H, Cecchi F, Rabe DC, Keer H, Martin AM, Liu Y, Gagnon R, Bonate P, Liu L, Gilmer T, Bottaro DP. Phase II study evaluating 2 dosing schedules of oral foretinib (GSK1363089), cMET/VEGFR2 inhibitor, in patients with metastatic gastric cancer. PLoS One. 2013;8(3):e54014. doi: 10.1371/journal.pone.0054014. Epub 2013 Mar 14. PubMed PMID: 23516391; PubMed Central PMCID: PMC3597709.
4: Logan TF. Foretinib (XL880): c-MET inhibitor with activity in papillary renal cell cancer. Curr Oncol Rep. 2013 Apr;15(2):83-90. doi: 10.1007/s11912-013-0299-3. Review. PubMed PMID: 23408121.
5: Choueiri TK, Vaishampayan U, Rosenberg JE, Logan TF, Harzstark AL, Bukowski RM, Rini BI, Srinivas S, Stein MN, Adams LM, Ottesen LH, Laubscher KH, Sherman L, McDermott DF, Haas NB, Flaherty KT, Ross R, Eisenberg P, Meltzer PS, Merino MJ, Bottaro DP, Linehan WM, Srinivasan R. Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma. J Clin Oncol. 2013 Jan 10;31(2):181-6. doi: 10.1200/JCO.2012.43.3383. Epub 2012 Dec 3. PubMed PMID: 23213094; PubMed Central PMCID: PMC3532390.
6: Shapiro GI, McCallum S, Adams LM, Sherman L, Weller S, Swann S, Keer H, Miles D, Müller T, Lorusso P. A Phase 1 dose-escalation study of the safety and pharmacokinetics of once-daily oral foretinib, a multi-kinase inhibitor, in patients with solid tumors. Invest New Drugs. 2013 Jun;31(3):742-50. doi: 10.1007/s10637-012-9881-z. Epub 2012 Oct 6. PubMed PMID: 23054208.
7: Seiwert T, Sarantopoulos J, Kallender H, McCallum S, Keer HN, Blumenschein G Jr. Phase II trial of single-agent foretinib (GSK1363089) in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Invest New Drugs. 2013 Apr;31(2):417-24. doi: 10.1007/s10637-012-9861-3. Epub 2012 Aug 24. PubMed PMID: 22918720; PubMed Central PMCID: PMC3589657.
8: Huynh H, Ong R, Soo KC. Foretinib demonstrates anti-tumor activity and improves overall survival in preclinical models of hepatocellular carcinoma. Angiogenesis. 2012 Mar;15(1):59-70. doi: 10.1007/s10456-011-9243-z. Epub 2011 Dec 21. PubMed PMID: 22187171.
9: Dufies M, Jacquel A, Robert G, Cluzeau T, Puissant A, Fenouille N, Legros L, Raynaud S, Cassuto JP, Luciano F, Auberger P. Mechanism of action of the multikinase inhibitor Foretinib. Cell Cycle. 2011 Dec 1;10(23):4138-48. doi: 10.4161/cc.10.23.18323. Epub 2011 Dec 1. PubMed PMID: 22101270.
10: Kataoka Y, Mukohara T, Tomioka H, Funakoshi Y, Kiyota N, Fujiwara Y, Yashiro M, Hirakawa K, Hirai M, Minami H. Foretinib (GSK1363089), a multi-kinase inhibitor of MET and VEGFRs, inhibits growth of gastric cancer cell lines by blocking inter-receptor tyrosine kinase networks. Invest New Drugs. 2012 Aug;30(4):1352-60. doi: 10.1007/s10637-011-9699-0. Epub 2011 Jun 8. PubMed PMID: 21655918.
