生物活性

• 靶点

  PDGFRβ IC50:2nM

  VEGFR2 IC50:80nM

• 描述VEGFR (vascular endothelial growth factor) and PDGFR (platelet-derived growth factor receptor) are critical roles in tumor growth and suvival via autocrine and paracrine loops, making them the well validated targets for the treatment of cancers. Sunitinib is a multiple RTKs inhibitor with IC50 values of 2nM and 80nM for VEGFR2 and PDGFRβ (measured by kinase activity)^[1], respectively, also shows inhibition against KIT and FLT3 receptor^[2]. The cellular kinase activity induced by VEGF/PDGF can be inhibited by Sunitinib with IC50 value of 5-50nM/10nM in 3T3 cells, while the PDGF-induced cell growth can be inhibited by Sunitinib with IC50 of 8nM^[1]. Daily oral administration of Sunitinib at dose of 80mg/kg reduced growth of established SF763T tumor xenografts in athymic mice, as well as suppressed Colo205 tumor growth. Consistent with the cellular kinase study, the inhibition by Sunitinib against p-PDGFRβ can be observed in tumor after a single dose at 80mg/kg in mice bearing SF767T tumors and mice bearing Colo205 tumors, as well as suppressed p-FLK1 in A375 xenograft mice dosed 40mg/kg Sunitinib^[2].
• 作用机制Sunitinib is an ATP-competitive multitargeted tyrosine kinase inhibitor.^[3]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  3T3 cells	-	Function assay	-	Inhibition of PDGF-induced BrdU incorporation in 3T3 cells with 0.1% bovine serum albumin, IC50=7 nM	12646019
  3T3 cells	-	Function assay	-	Inhibition of Vascular endothelial growth factor receptor in 3T3 cells, IC50=50 nM	12646019
  HEK293 cells	-	Function assay	-	Binding affinity to FLT3 catalytic domain expressed in HEK293 cells by competitive binding assay, Kd=0.47 nM	19754199

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• 动物研究
  剂量	Rat: 0.5 mg/kg[5] (p.o.), 1 mg/kg - 10 mg/kg[6] (p.o.) Mice: 40 mg/kg[7] (p.o.)
  给药途径	p.o.

• 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
  NCT00716820	-	-	Completed	-	-
  NCT01061411	Clear Cell Sarcoma of the Kidn... more >>ey Recurrent Renal Cell Carcinoma Stage III Renal Cell Cancer Stage IV Renal Cell Cancer Collapse <<	Phase 1	Completed	-	United States, California ... more >> City of Hope Comprehensive Cancer Center Duarte, California, United States, 91010 United States, New York Roswell Park Cancer Institute Buffalo, New York, United States, 14263 Netherlands Academ Zienkenhuis Bij De University Amsterdam, Netherlands, 1007 MB VU University Medical Center Amsterdam, Netherlands, 1081 HV Collapse <<
  NCT00330564	Von Hippel-Lindau Syndrome ... more >> Renal Cell Carcinoma Hemangioblastoma Collapse <<	Phase 2	Terminated(Slow accrual.)	-	United States, Texas ... more >> UT MD Anderson Cancer Center Houston, Texas, United States, 77030 Collapse <<

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• 参考文献

• [1] Sun L, Liang C, et al. Discovery of 5-[5-fluoro-2-oxo-1,2- dihydroindol-(3Z)-ylidenemethyl] -2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase. J Med Chem. 2003 Mar 27;46(7):1116-9.

  [2] Mendel DB, Laird AD, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res. 2003 Jan;9(1):327-37.

  [3] Shukla S, Robey RW, et al. Sunitinib (Sutent, SU11248), a small-molecule receptor tyrosine kinase inhibitor, blocks function of the ATP-binding cassette (ABC) transporters P-glycoprotein (ABCB1) and ABCG2. Drug Metab Dispos. 2009 Feb;37(2):359-65.

  [4] Zhou Q, Gallo JM. Differential effect of sunitinib on the distribution of temozolomide in an orthotopic glioma model. Neuro Oncol. 2009;11(3):301-10.