生物活性

• 靶点

  c-FMS IC50:146nM

  c-Kit IC50:140nM

  FGFR IC50:74nM

  PDGFR IC50:84nM

  VEGFR1 IC50:10nM

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• 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. Pazopanib hydrochloride is the hydrochloride form of Pazopanib. Pazopanib is a pan VEGFR inhibitor with IC50 values of 10nM, 30nM and 47nM for VEGFR1, VEGFR2 and VEGFR3 (measured by HTRF), respectively, less potent to c-Kit, PDGFR, FGFR and c-Fms with IC50 values of 74nM, 84nM, 140nM and 146nM. In cellular studies, Pazopanib inhibited VEGF/bFGF-induced proliferation of HUVECs with IC50 value of 21nM/720nM, as well as potently inhibited VEGF-induced the phosphorylation of VEGFR-2 with IC50 value of ∼8nM. As prediction by the inhibition of VEGFR and FGFR, matrigel plug assay showed that once-daily oral administration of Pazopanib at dose of 30mg/kg and 100mg/kg inhibited angiogenesis by 57% and 83%, respectively, in female swiss nu/nu mice, as well as achieved tumor inhibition by 32%, 59% and 69% in HT29 xenograft, 16%, 35% and 55% in A375P xenograft, 99%, 102% and 110% in HN5 xenograft at dose of 10mg/kg, 30mg/kg and 100mg/kg^[1].
• 作用机制Pazopanib is an ATP-competitive inhibitor of human VEGFR2.^[2]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  5637	-	Growth inhibitory assay	-	IC50=15.0 μM	23887605
  5637	20 μM	Autophagy assay	-	triggers the autophagic process	23887605
  5637	20 μM	Function assay	-	induces lysosomal-dependent necrosis	23887605

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• 动物研究
  剂量	Mice: 300 mg/kg[3] (i.p.), 10 mg/kg - 100 mg/kg[1] (p.o.)
  给药途径	i.p., p.o.
  动物药代数据	Animal Nude mice[2] Dose 30 mg/kg Administration p.o. Cmax 130 μM T1/2 4.6 h AUCinf 1500 μM·h

• 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
  NCT01027598	Non Small Cell Lung Cancer	Phase 2	Completed	-	United States, Florida ... more >> Florida Cancer Specialists Fort Myers, Florida, United States, 33901 United States, Georgia Suburban Hem Onc Lawrenceville, Georgia, United States, 30045 United States, Ohio Oncology Hematology Care Cincinnati, Ohio, United States, 45242 United States, South Carolina South Carolina Oncology Associates, PA Columbia, South Carolina, United States, 29210 United States, Tennessee Chattanooga Oncology Hematology Associates Chattanooga, Tennessee, United States, 37404 Family Cancer Center Collerville, Tennessee, United States, 38119 Tennessee Oncology, PLLC Nashville, Tennessee, United States, 37023 United States, Virginia Virginia Cancer Institute Richmond, Virginia, United States, 23235 Collapse <<
  NCT00788580	Unspecified Adult Solid Tumor,... more >> Protocol Specific Collapse <<	Phase 1	Withdrawn(Study was discontinu... more >>ed.) Collapse <<	-	-
  NCT01027598	-	-	Completed	-	-

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• 参考文献

• [1] Harris PA, Boloor A, et al. Discovery of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino] -2-pyrimidinyl] amino] -2-methyl-benzenesulfonamide (Pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor. J Med Chem. 2008 Aug 14;51(15):4632-40.

  [2] Kumar R, Knick VB, et al. Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Ther. 2007 Jul;6(7):2012-21.

  [3] Wang YK, Yang XN, et al. A metabolomic perspective of pazopanib-induced acute hepatotoxicity in mice. Xenobiotica. 2019 Jun;49(6):655-670.