生物活性

• 靶点

  c-FMS IC50:3nM

  VEGFR1 IC50:3nM

  VEGFR2 IC50:4nM

  FLT3 IC50:4nM

  PDGFRβ IC50:66nM

• 描述Linifanib is a muti-target inhibitor with IC50 values of 3nM, 3nM, 4nM, 4nM, 14nM and 66nM for VEGFR1, CSF-1R, VEGFR2, FLT3, c-Kit and PDGFRβ(measured by kinase assays), respectively. Linifanib showed in cellular inhibition on ligand-induced phosphorylation of PDGFR-βKDR and CSF-1R with IC50 values of 2nM, 31nM and 10nM, respectively, in 3T3 transfectants, as well as VEGF-induced proliferation with IC50 value of 0.2nM for human endothelial cells^[1]. The in vivo study showed that, consistent with the inhibition of VEGFR and PDGFRβby Linifanib, oral administration of Linifanib at dose of 7.5 and 15mg/kg, BID, significantly inhibited bFGF- and VEGF-induced increases of vessel density in the cornea. Oral treatment with Linifanib at dose ranging in 1.5-12.5mg/kg, BID, could significantly reduce the tumor growth or in several orthotopic tumor models, including MDA-231 and MDA-435LM xenograft mice and rat glioma, or enhance the anti-tumor effect of paclitaxel in the models^[1].
• 作用机制Linifanib can bind to the ATP-binding site of CSF-1R.^[2]

• 动物研究
  剂量	Mice: 25 mg/kg[3] (p.o., BID), 1.5 mg/kg - 15 mg/kg[1] (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Rats[4] Dogs[4] Monkeys[4] Dose 5 mg/kg (i.v./p.o.) 2.5 mg/kg (i.v./p.o.) 2.5 mg/kg (i.v./p.o.) Administration i.v. p.o. i.v. p.o. i.v. p.o. F 27% (p.o.) 47% (p.o.) 10.6% (p.o.) Vd 1.1 L/kg (i.v.) 1.2 L/kg (i.v.) 2.2 L/kg (i.v.) T1/2 3.6 h (i.v.) 2.0 h (i.v.) 3.1 h (i.v.) AUC 6.8 µg·h/ml (p.o.) 1.5 µg·h/ml (p.o.) 0.6 µg·h/ml (p.o.) CL 3.3 ml/min·kg (i.v.) 7.2 ml/min·kg (i.v.) 8.2 ml/min·kg (i.v.)