For research use only. Not for therapeutic Use.
<p style=/line-height:25px/>Foretinib (GSK1363089; XL880; EXEL-2880; GSK089) is an ATP-competitive inhibitor of HGFR and VEGFR, mostly for Met and KDR with IC50 of 0.4 nM and 0.9 nM. Less potent against Ron, Flt-1/3/4, Kit, PDGFRα/β and Tie-2, and little activity to FGFR1 and EGFR.<br>IC50 value: 0.4 nM/0.9 nM (Met/KDR) [1]<br>Target:<br>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].<br>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].</p>
| Catalog Number | I005091 |
| CAS Number | 849217-64-7 |
| Synonyms | 1-N/’-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide |
| Molecular Formula | C₃₄H₃₄F₂N₄O₆ |
| Purity | ≥95% |
| Target | VEGFR |
| Solubility | DMSO：≥ 38 mg/mL |
| Storage | 3 years -20C powder |
| IC50 | 0.4 nM/0.9 nM (Met/KDR) [1] |
| InChI | 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) |
| InChIKey | CXQHYVUVSFXTMY-UHFFFAOYSA-N |
| 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 |
| Reference | </br>1:A phase-I study of lapatinib in combination with foretinib, a c-MET, AXL and vascular endothelial growth factor receptor inhibitor, in human epidermal growth factor receptor 2 (HER-2)-positive metastatic breast cancer. Chia SK, Ellard SL, Mates M, Welch S, Mihalcioiu C, Miller WH Jr, Gelmon K, Lohrisch C, Kumar V, Taylor S, Hagerman L, Goodwin R, Wang T, Sakashita S, Tsao MS, Eisenhauer E, Bradbury P.Breast Cancer Res. 2017 May 2;19(1):54. doi: 10.1186/s13058-017-0836-3. PMID: 28464908 Free PMC Article</br>2:A Phase I/II Multicenter Study of Single-Agent Foretinib as First-Line Therapy in Patients with Advanced Hepatocellular Carcinoma. Yau TCC, Lencioni R, Sukeepaisarnjaroen W, Chao Y, Yen CJ, Lausoontornsiri W, Chen PJ, Sanpajit T, Camp A, Cox DS, Gagnon RC, Liu Y, Raffensperger KE, Kulkarni DA, Kallender H, Ottesen LH, Poon RTP, Bottaro DP.Clin Cancer Res. 2017 May 15;23(10):2405-2413. doi: 10.1158/1078-0432.CCR-16-1789. Epub 2016 Nov 7. PMID: 27821605 </br>3:Canadian Cancer Trials Group IND197: a phase II study of foretinib in patients with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2-negative recurrent or metastatic breast cancer. Rayson D, Lupichuk S, Potvin K, Dent S, Shenkier T, Dhesy-Thind S, Ellard SL, Prady C, Salim M, Farmer P, Allo G, Tsao MS, Allan A, Ludkovski O, Bonomi M, Tu D, Hagerman L, Goodwin R, Eisenhauer E, Bradbury P.Breast Cancer Res Treat. 2016 May;157(1):109-16. doi: 10.1007/s10549-016-3812-1. Epub 2016 Apr 26. PMID: 27116183 </br>4:Erratum to: 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. Shapiro GI, McCallum S, Adams LM, Sherman L, Weller S, Swann S, Keer H, Miles D, Müller T, Rabe DC, Cecchi F, Bottaro DP, LoRusso P.Invest New Drugs. 2015 Dec;33(6):1292. doi: 10.1007/s10637-015-0287-6. No abstract available. PMID: 26407571 </br>5:Population pharmacokinetics modeling and analysis of foretinib in adult patients with advanced solid tumors. Singh RP, Patel B, Kallender H, Ottesen LH, Adams LM, Cox DS.J Clin Pharmacol. 2015 Oct;55(10):1184-92. doi: 10.1002/jcph.546. Epub 2015 Jul 7. PMID: 25998042 </br>6:Foretinib inhibits angiogenesis, lymphangiogenesis and tumor growth of pancreatic cancer in vivo by decreasing VEGFR-2/3 and TIE-2 signaling. Chen HM, Tsai CH, Hung WC.Oncotarget. 2015 Jun 20;6(17):14940-52. PMID: 25909285 Free PMC Article</br>7:Foretinib is effective therapy for metastatic sonic hedgehog medulloblastoma. 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.Cancer Res. 2015 Jan 1;75(1):134-46. doi: 10.1158/0008-5472.CAN-13-3629. Epub 2014 Nov 12. PMID: 25391241 Free Article</br>8:[ROS1 fusion proteins, targets of foretinib]. Bénard J.Bull Cancer. 2014 Jan 1;101(1):4. French. No abstract available. PMID: 24649496 </br>9:Foretinib is a potent inhibitor of oncogenic ROS1 fusion proteins. Davare MA, Saborowski A, Eide CA, Tognon C, Smith RL, Elferich J, Agarwal A, Tyner JW, Shinde UP, Lowe SW, Druker BJ.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 Free PMC Article</br>10:Phase II study evaluating 2 dosing schedules of oral foretinib (GSK1363089), cMET/VEGFR2 inhibitor, in patients with metastatic gastric cancer. 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.PLoS One. 2013;8(3):e54014. doi: 10.1371/journal.pone.0054014. Epub 2013 Mar 14. PMID: 23516391 Free PMC Article |
