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 Malate is the Malate form of Sunitinib. 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	-	Kinase Assay	-	Inhibition of PDGF-induced BrdU incorporation with IC50 of 0.007 μM	12646019
  3T3	-	Growth Inhibition Assay	-	Inhibition of Platelet-derived growth factor induced 3T3 cell proliferation with IC50 of 0.01 μM	12646019
  3T3	-	Function Assay	-	Inhibition of Vascular endothelial growth factor receptor with IC50 of 0.05 μM	12646019

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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.
  动物药代数据	Animal Rats[8] Dose 2 mg/kg (i.v. or p.o.) Administration i.v. p.o. F 112 ± 34% (p.o.) T1/2 2.52 ± 0.04 h (i.v.) AUCtlast 896 ± 461 ng·h/ml (p.o.) Tmax 2.0 ± 2.0 h (p.o.) Cmax 177 ± 86 ng/ml (p.o.) AUC0→∞ 996 ± 439 ng·h/ml (i.v.) 1178 ± 691 ng·h/ml (p.o.) CLs 40 ± 23 ml/min/kg (i.v.)

• 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
  NCT00663559	Carcinoma Renal Cells	Phase 2	Completed	-	Spain ... more >> Hospital Central de Asturias Oviedo, Asturias, Spain, 33006 Hospital Parc Taulí Sabadell, Barcelona, Spain, 08208 Hospital CLINIC Barcelona, Spain, 08036 Hospital Reina Sofía Córdoba, Spain, 14004 Hospital de Jaén Jaén, Spain, 23007 Hospital Clínico San Carlos Madrid, Spain, 28040 Hospital lozano Blesa Zaragoza, Spain, 50009 Collapse <<
  NCT03097601	-	-	Active, not recruiting	December 30, 2019	France ... more >> Centre Antoine LACASSAGNE Nice, France, 06189 Collapse <<
  NCT01243359	Clear Cell Renal Cell Carcinom... more >>a Recurrent Renal Cell Cancer Stage I Renal Cell Cancer Stage II Renal Cell Cancer Stage III Renal Cell Cancer Stage IV Renal Cell Cancer Unspecified Adult Solid Tumor, Protocol Specific Collapse <<	Phase 1	Completed	-	United States, Maryland ... more >> Johns Hopkins University/Sidney Kimmel Cancer Center Baltimore, Maryland, United States, 21287 United States, Wisconsin University of Wisconsin Hospital and Clinics Madison, Wisconsin, United States, 53792 Collapse <<

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• 参考文献

• [1] 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.

  [2] 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.

  [3] 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.

  [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.

  [5] sunitinib malate

  [6] Blasi E, Heyen J, et al. Sunitinib, a receptor tyrosine kinase inhibitor, increases blood pressure in rats without associated changes in cardiac structure and function. Cardiovasc Ther. 2012 Oct;30(5):287-94.

  [7] Gotink KJ, Broxterman HJ, et al. Acquired tumor cell resistance to sunitinib causes resistance in a HT-29 human colon cancer xenograft mouse model without affecting sunitinib biodistribution or the tumor microvasculature. Oncoscience. 2014 Dec 15;1(12):844-53. eCollection 2014.

  [8] Sutent

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