Background
LY2874455 is a novel and potent FGFR inhibitor with IC50 value of 7 nM [1].
Fibroblast growth factor receptors (FGFRs) are receptors bind ligand of FGF family, which have a intracellular domain with tyrosine kinase activity. The binding of FGF triggers receptor dimerization and thus the activation of tyrosine kinase activity. Activated tyrosine kinase phosphorylates various downstream factors to induce downstream signaling, including FGF substrate 2 (FGS2). This signaling pathway contributes to FGFR-mediated cell proliferation and migration, which are involved in tumor formation and progression.
In HUVECs cell line expressing FGFR1 and RT-112 cell line expressing FGFR3, LY2874455 treatment resulted in inhibition of FGF2 and FGF9 induced Erk phosphorylation, which indicated the inhibitory activity of LY2874455 for FGFR1 and FGFR3 [1]. In SNU-16 and KATO-Ш cell line, the inhibition of FGFR2 phosphorylation was also observed, which indicated a direct inhibition by LY2874455 [2]. Additionally, when several multiple myeloma cancer cell lines were treated with LYS2874455, the cell lines with chromosomal translocation that resulted in overexpression of FGFR3 were significantly more susceptible to the inhibition of LY2874455 [2]. It suggested FGFR was the specific target of LY2874455 inhibition.
In RT-112, SNU-16, OPM-2 and NCI-H460 xenograft tumor model, treatment of LY2874455 twice a day (1.5 mg/kg and 3 mg/kg) resulted in significant dose-dependent reduction of cellular level of phosphorylated FGFR, and also regression of tumor growth. It indicated the inhibitory activity of LY2874455 in vivo [2].
Reference:
[1] Zhao, G S et al.?, A Novel, Selective Inhibitor of Fibroblast Growth Factor Receptors That Shows a Potent Broad Spectrum of Antitumor Activity in Several Tumor Xenograft Models. Molecular Cancer Therapeutics. 2011, 10(11): 2200-2210.
Protocol
|
Cell experiment [1]:
|
|
Cell lines
|
HUVECs and RT-112 cells, gastric cancer cell lines, SNU-16 and KATO-III
|
|
Preparation method
|
The solubility of this compound in DMSO is >22.2mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.
|
|
Reacting condition
|
37°C, 1 hour
|
|
Applications
|
LY2874455 potently inhibited the Erk phosphorylation induced by FGF2 and FGF9 in both HUVECs and RT-112 cell lines in a dose-dependent manner, with the IC50 values of 0.3 to 0.8 nmol/L. LY2874455 inhibited FGFR2 phosphorylation in SNU-16 and KATO-III cells, with estimated IC50 values of 0.8 and 1.5 nmol/L, respectively. LY2874455 inhibited the phosphorylation of FRS2, an immediate downstream target of FGFR in these cell lines, again with a similar potency of 0.8 to 1.5 nmol/L.
|
|
Animal experiment [1]:
|
|
Animal models
|
Mice xenografted with cancer cell lines with altered FGFR or FGF levels, RT-112 (overexpressing FGFR3), SNU-16 (amplified FGFR2), OPM-2 (overexpressing a mutant FGFR3), and NCI-H460 (a high level of FGF2)
|
|
Dosage form
|
1 mg/kg, 3 mg/kg, every day
|
|
Application
|
LY2874455 exhibited a rapid, robust, dose-dependent inhibition of tumor growth in all 4 models tested. LY2874455 caused a significant regression of tumor growth in the RT-112, SNU-16, and OPM-2 tumor models, especially when dosed at 3 mg/kg twice a daily.
|
|
Other notes
|
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
|
|
参考文献:
[1]. Zhao G, Li W, Chen D, et al. A novel, selective inhibitor of fibroblast growth factor receptors that shows a potent broad spectrum of antitumor activity in several tumor xenograft models[J]. Molecular cancer therapeutics, 2011, 10(11): 2200-2210.
|
没有评价数据