The FGFR (fibroblast growth factor receptor) family comprises four members, FGFR1, FGFR2, FGFR3 and FGFR4, ligand of which can induce cellular phosphorylation events, proliferation and potent antiangiogenic activity. PD166866 is a highly selective and nanomolar potent inhibitor of FGFR-1 tyrosine kinase with an IC50 value of 52.4nM (measure protein tyrosine kinase activity) and no effect on c-Src, platelet-derived growth factor receptor-b, EGFR or insulin receptor tyrosine kinases or on MAPK, PKC and CDK4 at concentrations as high as 50μM. Pre-treatment with PD 166866 on concentration of 10 or 100nM for 2h caused inhibition on autophosphorylation of FGFR1 induced by bFGF (25ng/ml) for 5 min in NIH 3T3 cells expressing endogenous FGFR1 and in L6 cells overexpressing the human FGFR1 tyrosine kinase, along with the inhibition of downstream p-ERK 1/2. Consistent with this, daily exposure to PD 166866 at concentrations 1-100nM for 8 consecutive days resulted in a concentration-related inhibition of bFGF-stimulated cell growth of L6 cells[1]. Another mechanism action of PD166866 on negative control of cell proliferation maybe due to its activation of the apoptotic pathway, suggested by specific point as evaluation of DNA damage, lipoperoxidation of the cell membrane and increase of expression of PARP, an enzyme directly involved in DNA repair[2].
作用机制
PD 166866 is an ATP competitive inhibitor of FGFR1.[1]
PD-166866 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HeLa cells
0.1 - 50 μM
24 h
To evaluate the cytotoxicity of PD-166866 on HeLa cells, the results showed that the drug significantly reduced cell viability, indicating its anti-proliferative effects.
J Exp Clin Cancer Res. 2009 Dec 11;28(1):151.
human induced pluripotent stem cells (hiPSCs)
1 μM
4 days
To evaluate the role of PD-166866 in the differentiation of hiPSCs into pancreatic islet-like cells (iPICs), the results showed that PD-166866 played an important role in iPIC differentiation.
Stem Cell Res Ther. 2023 Jan 5;14(1):1.
Valve interstitial cells (VICs)
1000 nM
2 h
To investigate the inhibitory effect of PD-166866 on FGF1- and FGF2-mediated Akt phosphorylation. Results showed that PD-166866 significantly inhibited FGF1- and FGF2-mediated Akt phosphorylation.
J Biol Eng. 2019 May 27;13:45.
Jurkat cells
4 μM
36 h
To study the effect of PD-166866 on Jurkat cells, results showed that PD-166866 treatment significantly increased the expression of ATF4.
Acta Pharmacol Sin. 2023 Nov;44(11):2282-2295.
Oli-neu oligodendrocytes
10 µM
24 h
To study the effects of PD166866 and/or IFN β-1a on the proliferation and cytotoxicity of Oli-neu oligodendrocytes. Results showed that PD166866 and IFN β-1a, either alone or in combination, significantly reduced cell proliferation, and PD166866 increased cytotoxicity.
Int J Mol Sci. 2022 Oct 12;23(20):12183.
PD-166866 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
NCG mice
Jurkat cell-derived xenograft model
Intraperitoneal injection
30 mg/kg
Every 2 days for 14 days
To study the effect of PD-166866 on T-ALL cells in vivo, results showed that PD-166866 did not significantly inhibit the growth of T-ALL cells.
36 to 96 hpf, 36 to 48 hpf, 48 to 72 hpf, 72 to 96 hpf
To study the effects of PD166866 on thyroid development, results showed that PD166866 had different effects on thyroid morphology and volume at different time windows.
FEBS Open Bio. 2021 May;11(5):1417-1427
Mice
Colorectal cancer liver metastasis model
Intraperitoneal injection
20 mg/kg
Once every other day for 3 weeks
PD-166866 significantly inhibited the expression of p-FGFR1, p-ERK1/2, EGR1, and FAPα
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