NVP-TAE 226 is a potentFAK inhibitor with IC50 of 5.5 nM, modestly potent to Pyk2 (IC50=3.5 nM) and 10- to 100-fold less potent against InsR, IGF-1R, ALK, and c-Met.
Both abnormal activity of FAK (focal adhesion kinase) and IGF-IR (Insulin-like growth factor-I receptor) contribute to highly infiltrative and rapid growth characteristics in tumors, as FAK can regulate tumor migration, while the expression of IGF-IR correlate with tumor grade and involved in proliferation and survival. NVP-TAE 226 is multiple-target tyrosine kinase inhibitor with IC50 of 5.5nM and 120-160nM for FAK and IGF-IR (measured by in vitro kinase assays), respectively. Treatment with NVP-TAE 226 at concentration of 0.25-1μM could dose-dependently inhibit extracellular matrix (ECM)–induced activation of FAK on its Tyr397 phosphorylation site, as well as IGF-1-induced activation of IGF-1/AKT signaling, shown as decreased p-IGF1R, p-AKT and p-ERK, in U87 cells. Also NVP-TAE 226 significant inhibited glioma cell growth and disrupted cell cycle distribution with a marked decline in cyclin B1 and p-cdc2 protein expression at concentration of 10μM, as well as induces apoptosis in glioma cells containing mut-p53 at concentration of 1μM, including U251, LN18 and LN229 cell lines. As prediction, inhibition of FAK by 1μM NVP-TAE 226 significantly decreased the invasive propensity of glioma cells U87, U87/EGFRvIII, U251, and LN18. Oral administration of NVP-TAE 226 at dose of 50mg/kg and 75mg/kg prolonged the survial of prolongs the survival of glioma cell LN229 xenograft animals[1].
作用机制
NVP-TAE 226 is a potent ATP-competitive inhibitor of several tyrosine protein kinases.[1]
NVP-TAE 226 细胞研究
细胞系
浓度
检测类型
检测时间
活动说明
数据源
BT474 cells
1 μM
Function assay
24 h
Induction of apoptosis in human BT474 cells assessed as cleavage of 89 kDa PARP at 1 uM after 24 hrs by Western blotting
18989950
HCT116 cells
Proliferation assay
48 h
Antiproliferative activity against human HCT116 cells after 48 hrs by WST-1 assay, IC50=0.4 μM
25180654
HUVEC
Function assay
72 h
Antiangiogenic activity in HUVEC assessed as inhibition of VEGF-stimulated proliferation after 72 hrs by WST-1 assay, IC50=1 μM
23845217
MDA-MB-231 cells
Proliferation assay
48 h
Antiproliferative activity against human MDA-MB-231 cells after 48 hrs by WST-1 assay, IC50=2.8 μM
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