Background
TAE226 (NVP-TAE226) is a selective inhibitor of FAK with IC50 value of 5.5 nM [1].
Focal Adhesion Kinase (FAK) also known as PTK2 protein tyrosine kinase 2 (PTK2) is a focal adhesion-associated protein kinase and plays an important role in cellular adhesion and spreading processes [1].
TAE226 (NVP-TAE226) is a potent FAK inhibitor and has a different selectivity with the reported FAK inhibitor PF-562271. When tested with glioma cell lines U87, U87/EGFR, U87/EGFRvIII and U251 that expressed different level of FAK, TAE226 (NVP-TAE226) showed effective inhibition on the growth of the 4 cell lines in a dose dependent manner (1 and 10 μmol/L) and U87/EGFR, as well as U87/EGFRvIII, which had higher p-FAK expression than U87 were more sensitive to TAE226 (NVP-TAE226). Then, it was shown that TAE226 (NVP-TAE226) treatment inhibited Glioma cell invasion and induced apoptosis when tested with U251 and LN18 cell lines [1]. In the medullary thyroid tumor cell line MZ-CRC-1, TAE226 (NVP-TAE226) (100 nM and 1000 nM) treatment for 72 h inhibited cell proliferation, prolonged cellular processes and decreased cell invasion ability [2].
In male nude mice model with U87 subcutaneous xenograft, administration of TAE226 (NVP-TAE226) (50 or 75 mg/kg) prolonged the median survival of animals by 7 days with significant difference compared with control group (29 days) [1].
It is also reported that TAE226 (NVP-TAE226) is a potent inhibitor for Pyk2 with IC50 value of 3.5 nM [1].
参考文献:
[1].? Liu, T.J., et al., Inhibition of both focal adhesion kinase and insulin-like growth factor-I receptor kinase suppresses glioma proliferation in vitro and in vivo. Mol Cancer Ther, 2007. 6(4): p. 1357-67.
[2].?? Plaza-Menacho, I., et al., Focal adhesion kinase (FAK) binds RET kinase via its FERM domain, priming a direct and reciprocal RET-FAK transactivation mechanism. J Biol Chem, 2011. 286(19): p. 17292-302.
Protocol
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Cell experiment [1]:
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Cell lines
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Human glioma cell lines U87, U87/EGFR, U87/vIII and U251
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Preparation method
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The solubility of this compound in DMSO is > 23.5mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below - 20 °C for several months.
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Reacting condition
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1 and 10 μM
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Applications
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In all human glioma cell lines tested, TAE226 significantly inhibited tumor growth in a concentration-dependent manner. Compared with U87 cells, U87/EGFR and U87/vIII cells with a higher level of p-FAK (Tyr397) were more sensitive to TAE226.
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Animal experiment [1]:
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Animal models
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Mice bearing intracranial glioma xenografts
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Dosage form
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50 and 75 mg/kg; p.o.; q.d. for 5 days and off for 2 days, for a duration of 4 weeks
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Applications
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In U87-engrafted mice, TAE226 at 50 or 75 mg/kg extended the median survival by 6 and 7 days, respectively. In LN229-engrafted mice, TAE226 significantly prolonged the median survival by 19 days.
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Other notes
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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.
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参考文献:
[1]. Liu, T.J., et al., Inhibition of both focal adhesion kinase and insulin-like growth factor-I receptor kinase suppresses glioma proliferation in vitro and in vivo. Mol Cancer Ther, 2007. 6(4): p. 1357-67.
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