Foretinib | XL880 | GSK1363089 | CAS#849217-64-7 | MET/VEGFR2 inhibitor

MedKoo Cat#: 201372 | Name: Foretinib

Description:

WARNING: This product is for research use only, not for human or veterinary use.

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.

Chemical Structure

Foretinib

CAS#849217-64-7 (free base)

Theoretical Analysis

MedKoo Cat#: 201372

Name: Foretinib

CAS#: 849217-64-7 (free base)

Chemical Formula: C34H34F2N4O6

Exact Mass: 632.2446

Molecular Weight: 632.65

Elemental Analysis: C, 64.55; H, 5.42; F, 6.01; N, 8.86; O, 15.17

Price and Availability

Size	Price	Availability
50mg	USD 120.00	Ready to ship
100mg	USD 190.00	Ready to ship
200mg	USD 350.00	Ready to ship
500mg	USD 750.00	Ready to ship
1g	USD 1,250.00	Ready to ship
2g	USD 2,250.00	Ready to ship
5g	USD 4,950.00	Ready to ship

Bulk Inquiry

Buy Now

Add to Cart

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

More Info

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#C21R05B12

QC Data

View QC data: current batch, Lot#C21R05B12

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

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	mg/mL	mM
Solubility
	DMSO	16.0	23.70
	Ethanol	25.0	39.50

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

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

Formulation protocol:

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: Daeschler SC, Zhang J, Gordon T, Borschel GH, Feinberg K. Foretinib mitigates cutaneous nerve fiber loss in experimental diabetic neuropathy. Sci Rep. 2022 May 19;12(1):8444. doi: 10.1038/s41598-022-12455-3. PMID: 35589940; PMCID: PMC9120083. 2: Fujino T, Suda K, Koga T, Hamada A, Ohara S, Chiba M, Shimoji M, Takemoto T, Soh J, Mitsudomi T. Foretinib can overcome common on-target resistance mutations after capmatinib/tepotinib treatment in NSCLCs with MET exon 14 skipping mutation. J Hematol Oncol. 2022 Jun 11;15(1):79. doi: 10.1186/s13045-022-01299-z. PMID: 35690785; PMCID: PMC9188708. 3: Gortany NK, Panahi G, Ghafari H, Shekari M, Ghazi-Khansari M. Foretinib induces G2/M cell cycle arrest, apoptosis, and invasion in human glioblastoma cells through c-MET inhibition. Cancer Chemother Pharmacol. 2021 Jun;87(6):827-842. doi: 10.1007/s00280-021-04242-0. Epub 2021 Mar 10. PMID: 33688998. 4: Kogata Y, Tanaka T, Ono YJ, Hayashi M, Terai Y, Ohmichi M. Foretinib (GSK1363089) induces p53-dependent apoptosis in endometrial cancer. Oncotarget. 2018 Apr 27;9(32):22769-22784. doi: 10.18632/oncotarget.25232. PMID: 29854314; PMCID: PMC5978264. 5: 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. PMID: 23408121. 6: Fu Y, Peng Y, Zhao S, Mou J, Zeng L, Jiang X, Yang C, Huang C, Li Y, Lu Y, Wu M, Yang Y, Kong T, Lai Q, Wu Y, Yao Y, Wang Y, Gou L, Yang J. Combination Foretinib and Anti-PD-1 Antibody Immunotherapy for Colorectal Carcinoma. Front Cell Dev Biol. 2021 Jul 8;9:689727. doi: 10.3389/fcell.2021.689727. PMID: 34307367; PMCID: PMC8298272. 7: Sohn SH, Kim B, Sul HJ, Choi BY, Kim HS, Zang DY. Foretinib Inhibits Cancer Stemness and Gastric Cancer Cell Proliferation by Decreasing CD44 and c-MET Signaling. Onco Targets Ther. 2020 Feb 3;13:1027-1035. doi: 10.2147/OTT.S226951. PMID: 32099405; PMCID: PMC7006849. 8: Ji X, Meng X, He Q, Xiang X, Shi Y, Zhu X. Foretinib Is Effective against Triple-Negative Breast Cancer Cells MDA-MB-231 In Vitro and In Vivo by Down- Regulating p-MET/HGF Signaling. Int J Mol Sci. 2023 Jan 1;24(1):757. doi: 10.3390/ijms24010757. PMID: 36614199; PMCID: PMC9821162. 9: Chen HM, Tsai CH, Hung WC. Foretinib inhibits angiogenesis, lymphangiogenesis and tumor growth of pancreatic cancer in vivo by decreasing VEGFR-2/3 and TIE-2 signaling. Oncotarget. 2015 Jun 20;6(17):14940-52. doi: 10.18632/oncotarget.3613. PMID: 25909285; PMCID: PMC4558127. 10: Chen GZ, Dai WS, Zhu HC, Song HM, Yang X, Wang YD, Min H, Lu Q, Liu S, Sun XC, Zeng XN. Foretinib Enhances the Radiosensitivity in Esophageal Squamous Cell Carcinoma by Inhibiting Phosphorylation of c-Met. J Cancer. 2017 Mar 12;8(6):983-992. doi: 10.7150/jca.18135. PMID: 28529610; PMCID: PMC5436250. 11: Goltsov AA, Fang B, Pandita TK, Maru DM, Swisher SG, Hofstetter WL. HER2 Confers Resistance to Foretinib Inhibition of MET-Amplified Esophageal Adenocarcinoma Cells. Ann Thorac Surg. 2018 Feb;105(2):363-370. doi: 10.1016/j.athoracsur.2017.09.003. Epub 2017 Dec 7. PMID: 29223420. 12: Wang P, Zhang Y, Xiang R, Yang J, Xu Y, Deng T, Zhou W, Wang C, Xiao X, Wang S. Foretinib is effective in acute myeloid leukemia by inhibiting FLT3 and overcoming secondary mutations that drive resistance to quizartinib and gilteritinib. Cancer Res. 2024 Jan 17. doi: 10.1158/0008-5472.CAN-23-1534. Epub ahead of print. PMID: 38231480. 13: Faria CC, Golbourn BJ, Dubuc AM, Remke M, Diaz RJ, Agnihotri S, Luck A, Sabha N, Olsen S, Wu X, Garzia L, Ramaswamy V, Mack SC, Wang X, Leadley M, Reynaud D, Ermini L, Post M, Northcott PA, Pfister SM, Croul SE, Kool M, Korshunov A, Smith CA, Taylor MD, Rutka JT. Foretinib is effective therapy for metastatic sonic hedgehog medulloblastoma. Cancer Res. 2015 Jan 1;75(1):134-46. doi: 10.1158/0008-5472.CAN-13-3629. Epub 2014 Nov 12. PMID: 25391241. 14: 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. 15: 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. PMID: 22187171. 16: Hassan MS, Williams F, Awasthi N, Schwarz MA, Schwarz RE, Li J, von Holzen U. Combination effect of lapatinib with foretinib in HER2 and MET co-activated experimental esophageal adenocarcinoma. Sci Rep. 2019 Nov 26;9(1):17608. doi: 10.1038/s41598-019-54129-7. PMID: 31772236; PMCID: PMC6879590. 17: Grojean M, Schwarz MA, Schwarz JR, Hassan S, von Holzen U, Zhang C, Schwarz RE, Awasthi N. Targeted dual inhibition of c-Met/VEGFR2 signalling by foretinib improves antitumour effects of nanoparticle paclitaxel in gastric cancer models. J Cell Mol Med. 2021 Jun;25(11):4950-4961. doi: 10.1111/jcmm.16362. Epub 2021 May 3. PMID: 33939252; PMCID: PMC8178268. 18: 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. PMID: 24218589; PMCID: PMC3845150. 19: 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. PMID: 22101270. 20: Nishiyama A, Yamada T, Kita K, Wang R, Arai S, Fukuda K, Tanimoto A, Takeuchi S, Tange S, Tajima A, Furuya N, Kinoshita T, Yano S. Foretinib Overcomes Entrectinib Resistance Associated with the NTRK1 G667C Mutation in NTRK1 Fusion-Positive Tumor Cells in a Brain Metastasis Model. Clin Cancer Res. 2018 May 15;24(10):2357-2369. doi: 10.1158/1078-0432.CCR-17-1623. Epub 2018 Feb 20. PMID: 29463555.