生物活性

• 靶点

  VEGFR3 IC50:3nM

  VEGFR2 IC50:0.5nM

  VEGFR1 IC50:5nM

• 描述VEGF/VEGFR (vascular endothelial growth factor vascular endothelial growth factor receptor) pathway plays a key role in tumor angiogenesis by promotion of vascular and lymphatic endothelial, as well as survival, and invasion, thus resulting in neovascularization, tumor growth and metastasis. In addition, blockade of additional proangiogenic receptor tyrosine kinases, including PDGFR and FGFR, may improve long-term clinical outcomes. Cediranib is a multiple RTKs inhibitor with IC50 values of <0.001μM, 0.005μM, ≤0.003μM, 0.002μM and 0.005μM for VEGFR-2, VEGFR-1, VEGFR-3, c-Kit and PDGFR-β(measured kinase activity), respectively, less potent to PDGFR-α, CSF-1R, FGFR1, Src and Abl with IC50 values of 0.036nM, 0.11nM, 0.026nM, 0.13nM and 0.26nM, respectively. The kinase activity inhibition by Cediranib can be observed through the suppression of phosphorylation on KDR (HUVEC), c-Kit (NCI-H526), PDGFR-α (MG63), PDGFR-β (MG63), CSF-1R (NIH3T3/CSF1R) and EGFR (KB) with IC50 values of 0.0005, 0.001, 0.005, 0.008, 0.21 and 1.1μM, respectively, in cellular study. Consistent with its selectivity on VEGFR, Cediranib inhibited VEGF-stimulated HUVEC proliferation most potently with IC50 value of 0.4nM, versus IC50 values of 110nM/500nM for bFGF-/EGF-induced HUVEC proliferation, as well as 40nM PDGF-induced MG63 proliferation. Also through the inhibition of VEGFR, Cediranib inhibited vessel branching, length, and area with mean IC50 values of 0.1nM, 0.1nM and 0.2nM in in vitro study, as well as completely abolished VEGF-driven angiogenesis at 6mg/kg/day in in vivo models. The effect of Cediranib-induced hypertrophy in bone growth plate and inhibition on luteal development in ovary (5mg/kg, orally) further confirmed its inactivation of VEGF-induced angiogenesis within complex physiologic settings. Cediranib showed broad-spectrum anti-tumor activity as oral administration of Cediranib at dose of 1.5,3 and 6mg/kg once daily inhibited growth of all human tumor xenografts examined, including SW620 (colon), Calu-6 (lung), PC-3 (prostate), MDA-MB-231 (breast) and SKOV-3 (ovary), with vascular regression observed in Calu-6 lung tumor xenografts at dose of 6mg/kg^[1].
• 作用机制Cediranib is an ATP-competitive inhibitor of KDR tyrosine kinase.^[1]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  HUVEC cell	-	Proliferation assay	3 days	Inhibition of VEGF-stimulated HUVEC cell proliferation treated before 2 hrs of VEGF challenge assessed after 3 days by [3H]thymidine incorporation assay, ED50=12 nM	19101155

• 动物研究
  剂量	Mice: 1.5 mg/kg, 3 mg/kg[1] (p.o.), 1 mg/kg - 25 mg/kg[2] (p.o.); 0.75 mg/kg - 5 mg/kg[3] (i.p.)
  给药途径	p.o., i.p.

• 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
  NCT00691730	Unspecified Adult Solid Tumor,... more >> Protocol Specific Collapse <<	Not Applicable	Active, not recruiting	December 2018	Canada, Alberta ... more >> Tom Baker Cancer Centre Calgary, Alberta, Canada, T2N 4N2 Canada, Ontario London Regional Cancer Program London, Ontario, Canada, N6A 4L6 Mount Sinai Hospital Toronto, Ontario, Canada, M5G 1X5 University Health Network-Princess Margaret Hospital Toronto, Ontario, Canada, M5G 2M9 Collapse <<
  NCT00310089	Breast Cancer	Not Applicable	Completed	-	United States, Maryland ... more >> Warren Grant Magnuson Clinical Center - NCI Clinical Studies Support Bethesda, Maryland, United States, 20892-1182 United States, New Jersey Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School New Brunswick, New Jersey, United States, 08903 Collapse <<
  NCT02910843	Rectal Cancer	Phase 1	Recruiting	December 2022	Switzerland ... more >> St. Claraspital Basel Recruiting Basel, Switzerland, 4016 Contact: Dieter Köberle, MD    +41 61 685 85 85    dieter.koeberle@claraspital.ch    Principal Investigator: Dieter Köberle, MD          Universitätsspital Basel Recruiting Basel, Switzerland, 4031 Contact: Viviane Hess, Prof    +41 61 265 50 74    viviane.hess@usb.ch    Principal Investigator: Viviane Hess, Prof          Inselspital Bern Recruiting Bern, Switzerland, 3010 Contact: Martin D. Berger, MD    +41 31 632 41 14    martin.berger@insel.ch    Principal Investigator: Martin D. Berger, MD          Kantonsspital Graubünden Recruiting Chur, Switzerland, 7000 Contact: Ioannis Metaxas, MD    +41 81 256 66 46    ioannis.metaxas@ksgr.ch    Principal Investigator: Ioannis Metaxas, MD          Kantonsspital Luzern Recruiting Luzern, Switzerland, 6000 Contact: Ralph Winterhalder, MD    +41 41 205 58 75    ralph.winterhalder@ksl.ch    Principal Investigator: Ralph Winterhalder, MD          Kantonsspital St. Gallen Recruiting St. Gallen, Switzerland, 9007 Contact: Markus Jörger, MD    +41 71 494 29 22    markus.joerger@kssg.ch    Principal Investigator: Markus Jörger, MD          UniversitätsSpital Zürich Recruiting Zurich, Switzerland, 8091 Contact: Bernhard Pestalozzi, Prof    +41 (0)44 255 34 40    bernhard.pestalozzi@usz.ch    Principal Investigator: Bernhard Pestalozzi, Prof Collapse <<

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