生物活性

• 靶点

  FGFR3 IC50:150nM

  FGFR4 IC50:3nM

• 描述The FGFR (fibroblast growth factor receptor) family, comprising four members FGFR1 - 4, plays critical roles in a variety of normal developmental and physiological processes. The FGF19-FGFR4 signaling axis has been implicated in the pathogenesis of several cancers, including hepatocellular carcinomas in mice and potentially in humans. BLU9931 is exquisitely selective for FGFR4, with IC50 value of 3 nM for FGFR4, versus other FGFR family members (IC50 = 150 nM for FGFR3) and all other kinases. Treatment with BLU9931 demonstrated selective, potent and dose-dependent reduction of phosphorylation of FGFR4 signaling pathway components, including FRS2, MAPK and AKT, with complete inhibition at concentration≥10 nM in MDA-MB-453 cells . BLU9931 showed anti-proliferative effect on HCC cell lines expressing an intact FGFR4 signaling complex with EC50 values < 1 μM. BLU9931 exhibited durable pathway inhibition in Hep3B cells, as leading to decreased levels of pFRS2 and pMAPK brief exposure, as well as a prolonged effect of an increased expression of CYP7A1 mRNA, the more distal biomarker of FGF19/FGFR4 signaling, due to reversal of a negative feedback loop. Oral administration of BLU9931 twice daily for 21 days resulted in dose-dependent growth inhibition of tumors at dose of 10, 30 and 100 mg/kg in Hep 3B xenograft mice. Same with that, twice-daily treatment with BLU9931 at dose of 10 - 300 mg/kg led to tumor regression in the FGF19-overexpressing PDX-derived xenograft LIXC012^[1].
• 作用机制BLU9931 can form a covalent bond with Cys552 in the ATP-binding pocket of FGFR4^[1].

• 动物研究
  剂量	Mice[1] (p.o.): min = 10 mg/kg, max = 300 mg/kg
  给药途径	p.o.
  动物药代数据	Animal Mice[1] Dose 1 mg/kg (i.v.) 10 mg/kg (p.o.) Administration i.v. p.o. T1/2 1.1 h (i.v.) 2.3 h (p.o.) Vdss 1.3 L/kg (i.v.) F 18% (p.o.) AUC 815 ng·h/ml (i.v.) 1362 ng·h/ml (p.o.) CL 20 ml/min/kg (i.v.)