生物活性

• 靶点

  c-Kit IC50:6.7nM

  c-Met IC50:0.4nM

  FLT3 IC50:3.6nM

  PDGFRα IC50:3.6nM

  PDGFRβ IC50:9.6nM

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• 描述The overexpression and activation of the Met receptor and its ligand HGF (hepatocyte growth factor) are associated with a wide variety of human malignancies. Meanwhile, it is found that VEGFRs can cooperate with Met to induce tumor invasion and vascularization. Foretinib is a multiple RTKs inhibitor with IC50 values of 0.4, 0.9/2.8 and 3nM for Met, VEGFR2/3 and Ron, less potent to Tie-2, Flt-3, PDGFRα, KIT, VEGFR1, PDGFRβ with IC50 values of 1.1nM, 3.6nM, 3.6nM, 6.7nM, 6.8nM and 9.6nM, with almost no inhibition of FGFR1 or EGFR (measured by in vitro kinase assay). Potent inhibition of p-Met by Foretinib with IC50 values of 23 and 21nM in PC-3 and B16F10 cells, as well as the suppression of p-ERK and p-VEGFR2 induced by VEGF with IC50 of 16nM in HUVECs can be observed, suggesting the cellular RTKs inhibition. Foretinib can block HGF-induced migration with IC50 value of 44nM, as well as inhibit the anchorage-independent tumor cell colony growth of B16F10 cells with IC50 of 40nM. A further study on Inhibition of endothelial tubule formation and migration by Foretinib showed that Foretinib at concentration of 5nM or higher can both inhibit VEGF-induced tubule formation and block VEGF- or HGF-stimulated migration of HMVEC-L cells. Once daily oral administration of Foretinib at dose of 30 and 100mg/kg reduced lung surface tumor burden by 50% and 58%, respectively, in mice intravenously implanted B16F10 cells. Similarly, Foretinib at dose of 30 and 100mg/kg resulted in tumor growth inhibition of 64% and 87%, respectively, in mice bearing B16F10 solid tumors^[1].
• 作用机制Foretinib is an ATP-competitive inhibitor of HGFR and VEGFR.^[1]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  A172	100/300/900 nM	Function Assay	1 h	inhibits the phosphorylation of MerTK	24658326
  A172	100/300/900 nM	Function Assay	1 h	inhibits the activity of Axl, Tyro3	24658326
  A172	100/300/900 nM	Function Assay	1 h	decreases Akt phosphorylation in a concentration dependent manner	24658326

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• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01068587	Lung Cancer	Phase 1 Phase 2	Completed	-	Canada, British Columbia ... more >> BCCA - Vancouver Cancer Centre Vancouver, British Columbia, Canada, V5Z 4E6 Canada, Ontario Juravinski Cancer Centre at Hamilton Health Sciences Hamilton, Ontario, Canada, L8V 5C2 Ottawa Health Research Institute - General Division Ottawa, Ontario, Canada, K1H 8L6 Univ. Health Network-Princess Margaret Hospital Toronto, Ontario, Canada, M5G 2M9 Collapse <<
  NCT00725712	Neoplasms, Gastrointestinal Tr... more >>act Collapse <<	Phase 2	Completed	-	United States, Alabama ... more >> GSK Investigational Site Birmingham, Alabama, United States, 35294 United States, Arizona GSK Investigational Site Scottsdale, Arizona, United States, 85258 United States, California GSK Investigational Site Los Angeles, California, United States, 90024 GSK Investigational Site Stanford, California, United States, 94305 United States, District of Columbia GSK Investigational Site Washington, D.C., District of Columbia, United States, 20007 United States, Georgia GSK Investigational Site Atlanta, Georgia, United States, 30309 United States, Illinois GSK Investigational Site Chicago, Illinois, United States, 60637 United States, Massachusetts GSK Investigational Site Boston, Massachusetts, United States, 02114 United States, Michigan GSK Investigational Site Detroit, Michigan, United States, 48201 United States, Montana GSK Investigational Site Billings, Montana, United States, 59101 United States, New Mexico GSK Investigational Site Albuquerque, New Mexico, United States, 87131 United States, New York GSK Investigational Site New York, New York, United States, 10016 GSK Investigational Site New York, New York, United States, 10021 United States, North Carolina GSK Investigational Site Durham, North Carolina, United States, 27710 United States, Oregon GSK Investigational Site Portland, Oregon, United States, 97239 United States, Texas GSK Investigational Site Austin, Texas, United States, 78705 United States, Wisconsin GSK Investigational Site Madison, Wisconsin, United States, 53792 Collapse <<
  NCT00725712	-	-	Completed	-	-

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• 参考文献

• [1] Qian F, Engst S, et al. 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;69(20):8009-16.