生物活性

• 靶点

  FGFR1 IC50:0.2nM

  FGFR2 IC50:2.5nM

  FGFR3 IC50:1.8nM

• 描述The FGFR (fibroblast growth factor receptor) family, comprising four members, FGFR1, FGFR2, FGFR3 and FGFR4, belongs to the RTKs which serve as high affinity receptors for FGFs controlling cell proliferation, migration, apoptosis and differentiation. AZD4547 is a highly potent inhibitor of FGFR1-3 with IC50 values of 0.2nM, 2.5nM, and 1.8nM and displays weaker activity against FGFR4 (IC50=165nM). AZD4547 has potent in vitro antiproliferative effects with IC50 values ranged from 18nM to 281nM, as well as inhibition on FGFR auto-phosphorylation downstream p-MAPK, p-FRS2 and p-PLCγ induced by FGF, on tumor cell lines with deregulated FGFR expression as KG1a expressing a truncated wild-type FGFR1 fusion protein, Sum52-PE cells expressing wild-type FGFR2 and KMS11 cells expressing translocated/Y373C mutated FGFR3 protein, but no effect on MCF7 cells with no identified defects in FGFR expression or signaling. Twice daily oral administration of AZD4547 at dose of 3mg/kg caused 53% tumor growth inhibition while doses of 12.5mg/kg once daily and 6.25 mg/kg twice daily resulted in complete tumor stasis in female SCID mice bearing KMS11 tumors. 12.5mg/kg once daily AZD4547 resulted in 65% tumor growth inhibition in KG1a model. The pharmacodynamic effect of AZD4547 can be shown by decreased p-FGFR3 in mice, within 15 minutes of drug administration^[1].
• 作用机制AZD4547 competes with ATP for binding to FGF receptors 1, 2 and 3, thus inhibiting autophosphorylation and downstream signaling.^[2]

• 动物研究
  剂量	Mice: 1.5 mg/kg - 50 mg/kg[1] (p.o.)
  给药途径	p.o.