生物活性

• 靶点

  FGFR1 IC50:0.9nM

  FGFR2 IC50:1.4nM

  FGFR3 IC50:1nM

• 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. BGJ398 is a selective and potent inhibitor of FGFRs with IC50 values of 1 nM for FGFR11-3 and 60 nM for FGFR4, as well as 4.9 nM for FGFR3-K650E mutant (measured by purified recombinant enzymes). Treatment with BGJ398 in cell lysate from HEK293 cells transfected with FGFRs resulted in inhibition on autophosphorylation on specific tyrosine residues of FGFR 1 - 3 with IC50 values below 5 nM. Consistent with the in vitro study, BGJ398 inhibited the proliferation of the FGFR1-, FGFR2-, and FGFR3-dependent BaF3 cells with IC50 values ranged from 0.7 - 52.2 nM depended by different FGFR isoforms. Daily oral treatment with BGJ398 at dose of 10 or 30 mg/kg for 12 consecutive days induced tumor growth inhibition in the orthotopic xenograft bladder cancer model. Similarly, nearly complete tumor stasis was achieved by oral treatment of BGJ398 at dose of 5, 10 and 15 mg/kg in RT112 human bladder cancer xenografted rats^[1].
• 作用机制BGJ398 binds with ATP-binding pocket of FGFR3^[1].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  AN3CA	-	Growth Inhibition Assay	-	IC50=1.00 ± 0.20 μM	23443805
  ECC1	-	Growth Inhibition Assay	-	IC50=6.74 ± 0.59 μM	23443805
  EFE184	-	Growth Inhibition Assay	-	IC50=8.04 ± 0.69 μM	23443805

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• 动物研究
  剂量	Rat[1] (p.o.): 4.25 mg/kg, 8.51 mg/kg; Mice: 5 mg/kg[1] (i.v.), 20 mg/kg[1] (p.o.), 50 mg/kg[2] (p.o.)
  给药途径	i.v., p.o.
  动物药代数据	Animal Nude mice[1] Rats[1] Dose 5 mg/kg (i.v.) 20 mg/kg (p.o.) 5 mg/kg (i.v.) 10 mg/kg (p.o.) Administration i.v. p.o. i.v. p.o. Cmax 0.86 μM (i.v.) 0.42 μM (p.o.) 0.97 μM (i.v.) 0.26 μM (p.o.) T1/2 9.3 h (i.v.) 4.3 h (p.o.) 4.5 h (i.v.) 4.8 h (p.o.) F 32% (p.o.) 51% (p.o.) Tmax 1 h (p.o.) 4 h (p.o.) Vss 26 L/kg (i.v.) Vss 9.6 L/kg (i.v.) CL 3.3 L/h/kg (i.v.) 3.6 L/h/kg (i.v.) AUC(normalized to 1 mg/kg) 0.6 μM·h (i.v.) 0.18 μM·h (p.o.) 0.49 μM·h (i.v.) 0.25 μM·h (p.o.)

• 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
  NCT01820364	Melanoma	Phase 2	Terminated(Study was withdrawn... more >> due to scientific and business considerations.) Collapse <<	-	United States, Tennessee ... more >> Sarah Cannon Research Institute Onc Dept Nashville, Tennessee, United States, 37203 Australia, Victoria Novartis Investigative Site East Melbourne, Victoria, Australia, 3002 Canada, Alberta Novartis Investigative Site Edmonton, Alberta, Canada, T6G 1Z2 Germany Novartis Investigative Site Heidelberg, Germany, 69120 Spain Novartis Investigative Site Barcelona, Catalunya, Spain, 08035 Switzerland Novartis Investigative Site Zuerich, Switzerland, 8091 Collapse <<
  NCT01820364	-	-	Terminated(Study was withdrawn... more >> due to scientific and business considerations.) Collapse <<	-	-
  NCT02159066	Melanoma	Phase 2	Active, not recruiting	March 30, 2019	United States, Arizona ... more >> Mayo Clinic - Arizona onc Dept Scottsdale, Arizona, United States United States, California University of California at Los Angeles Onc Dept Los Angeles, California, United States, 90095 United States, Massachusetts Massachusetts General Hospital Dept of Onc. Boston, Massachusetts, United States, 02115 United States, New York Memorial Sloan Kettering Cancer Center Dept Oncology New York, New York, United States, 90033 United States, Oregon Oregon Health & Science University Onc. Dept Portland, Oregon, United States, 97239 United States, Tennessee Sarah Cannon Research Institute Onc. Dept Nashville, Tennessee, United States, 37203 Australia, Victoria Array BioPharma Investigative Site East Melbourne, Victoria, Australia, 3002 Canada, Ontario Array BioPharma Investigative Site Toronto, Ontario, Canada, M5G 2M9 Canada, Quebec Array BioPharma Investigative Site Montreal, Quebec, Canada, H3T 1E2 Germany Array BioPharma Investigative Site Heidelberg, Germany, 69120 Array BioPharma Investigative Site Köln, Germany, 50937 Array BioPharma Investigative Site Muenchen, Germany, 80336 Array BioPharma Investigative Site Würzburg, Germany, 97080 Italy Array BioPharma Investigative Site Napoli, Italy, 80131 Netherlands Array BioPharma Investigative Site Amsterdam, Netherlands, 1066 CX Spain Array BioPharma Investigative Site Barcelona, Catalunya, Spain, 08035 Switzerland Array BioPharma Investigative Site Zuerich, Switzerland, 8091 United Kingdom Array BioPharma Investigative Site Oxford, United Kingdom, OX3 7LJ Collapse <<

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• 参考文献

• [1] Guagnano V, Furet P, et al. Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase. J Med Chem. 2011 Oct 27;54(20):7066-83.

  [2] Xiao L, Du E, et al. Inhibition of FGFR Signaling Partially Rescues Hypophosphatemic Rickets in HMWFGF2 Tg Male Mice. Endocrinology. 2017 Oct 1;158(10):3629-3646.