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TAE226 (NVP-TAE226)

FAK inhibitor,potent and ATP-competitive CAS# 761437-28-9

TAE226 (NVP-TAE226)

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Quality Control of TAE226 (NVP-TAE226)

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Chemical structure

TAE226 (NVP-TAE226)

3D structure

Chemical Properties of TAE226 (NVP-TAE226)

Cas No. 761437-28-9 SDF Download SDF
PubChem ID 9934347 Appearance Powder
Formula C23H25ClN6O3 M.Wt 468.94
Type of Compound N/A Storage Desiccate at -20°C
Synonyms TAE226
Solubility DMSO : 50 mg/mL (106.62 mM; Need ultrasonic)
H2O : < 0.1 mg/mL (insoluble)
Chemical Name 2-[[5-chloro-2-(2-methoxy-4-morpholin-4-ylanilino)pyrimidin-4-yl]amino]-N-methylbenzamide
SMILES CNC(=O)C1=CC=CC=C1NC2=NC(=NC=C2Cl)NC3=C(C=C(C=C3)N4CCOCC4)OC
Standard InChIKey UYJNQQDJUOUFQJ-UHFFFAOYSA-N
Standard InChI InChI=1S/C23H25ClN6O3/c1-25-22(31)16-5-3-4-6-18(16)27-21-17(24)14-26-23(29-21)28-19-8-7-15(13-20(19)32-2)30-9-11-33-12-10-30/h3-8,13-14H,9-12H2,1-2H3,(H,25,31)(H2,26,27,28,29)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of TAE226 (NVP-TAE226)

DescriptionTAE226 (NVP-TAE226) is a potent inhibitor of FAK with an IC50 value of 5.5 nM.
TargetsPYK2FAKInsulin ReceptorIGF-1Rc-Met  
IC503.5 nM5.5 nM43.5 nM140 nM160 nM  

Protocol

Cell Assay [1]
Glioma cell cultures are harvested with 0.05% trypsin and seeded in triplicate at 2×104 in 24-well culture plates for 24 h before drug treatment. Culture medium is used for mock treatment. Cells are harvested at the indicated day after treatment, and viable cells are counted using the Vi-cell viability analyzer. The antiproliferative activity of NVP-TAE 226 (ranging from 0.25 to 1 μM) on cells growing in culture is determined using a tetrazolium-based colorimetric MTT assay[1].

Animal Administration [1]
Mice[1] Male nude mice used for this study are 6 to 8 weeks old. In DMEM/F12 serum-free media (5 μL), 5×105 of U87 cells and 1×106 of LN229 cells per mouse are implanted intracranially through a guide-screw system. Four days after injection of the tumor cells, mice are randomized into three groups for each cell line (n=6). Mice in group 1 are treated with 50 mg/kg NVP-TAE 226 in 200 μL of 0.5% methylcellulose, via an oral gavage. The mice in group 2 receive 75 mg/kg NVP-TAE 226 in 200 μL of 0.5% methylcellulose. The mice in group 3 the same vehicle used for administration of NVP-TAE 226 (control). Treatment frequency is once a day for 5 days and off for 2 days, for a duration of 4 weeks. Mice are monitored daily. Mice are euthanized when they are moribund, and the whole brain is extracted for rapid freezing in liquid nitrogen and storage at -70°C.

References:
[1]. Liu TJ, 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), 1357-1367. [2]. Delimont D, et al. Laminin α2-mediated focal adhesion kinase activation triggers Alport glomerular pathogenesis. PLoS One. 2014 Jun 10;9(6):e99083.

TAE226 (NVP-TAE226) Dilution Calculator

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Preparing Stock Solutions of TAE226 (NVP-TAE226)

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.1325 mL 10.6623 mL 21.3247 mL 42.6494 mL 53.3117 mL
5 mM 0.4265 mL 2.1325 mL 4.2649 mL 8.5299 mL 10.6623 mL
10 mM 0.2132 mL 1.0662 mL 2.1325 mL 4.2649 mL 5.3312 mL
50 mM 0.0426 mL 0.2132 mL 0.4265 mL 0.853 mL 1.0662 mL
100 mM 0.0213 mL 0.1066 mL 0.2132 mL 0.4265 mL 0.5331 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on TAE226 (NVP-TAE226)

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].

References:
[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.

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References on TAE226 (NVP-TAE226)

Inhibition of both focal adhesion kinase and insulin-like growth factor-I receptor kinase suppresses glioma proliferation in vitro and in vivo.[Pubmed:17431114]

Mol Cancer Ther. 2007 Apr;6(4):1357-67.

Multiple genetic aberrations in human gliomas contribute to their highly infiltrative and rapid growth characteristics. Focal adhesion kinase (FAK) regulates tumor migration and invasion. Insulin-like growth factor-I receptor (IGF-IR), whose expression correlates with tumor grade, is involved in proliferation and survival. We hypothesized that inhibiting the phosphorylation of FAK and IGF-IR by NVP-TAE226 (hereafter called TAE226), a novel dual tyrosine kinase inhibitor of FAK and IGF-IR, would suppress the growth and invasion of glioma cells. In culture, TAE226 inhibited extracellular matrix-induced autophosphorylation of FAK (Tyr(397)). TAE226 also inhibited IGF-I-induced phosphorylation of IGF-IR and activity of its downstream target genes such as MAPK and Akt. TAE226 retarded tumor cell growth as assessed by a cell viability assay and attenuated G(2)-M cell cycle progression associated with a decrease in cyclin B1 and phosphorylated cdc2 (Tyr(15)) protein expression. TAE226 treatment inhibited tumor cell invasion by at least 50% compared with the control in an in vitro Matrigel invasion assay. Interestingly, TAE226 treatment of tumor cells containing wild-type p53 mainly exhibited G(2)-M arrest, whereas tumor cells bearing mutant p53 underwent apoptosis. Induction of apoptosis by TAE226 was substantiated by detection of caspase-3/7 activation and poly(ADP-ribose) polymerase cleavage and by an Annexin V apoptosis assay. More importantly, TAE226 treatment significantly increased the survival rate of animals in an intracranial glioma xenograft model. Collectively, these data show that blocking the signaling pathways of FAK and IGF-IR with TAE226 has the potential to be an efficacious treatment for human gliomas.

Focal adhesion kinase (FAK) binds RET kinase via its FERM domain, priming a direct and reciprocal RET-FAK transactivation mechanism.[Pubmed:21454698]

J Biol Chem. 2011 May 13;286(19):17292-302.

Whether RET is able to directly phosphorylate and activate downstream targets independently of the binding of proteins that contain Src homology 2 or phosphotyrosine binding domains and whether mechanisms in trans by cytoplasmic kinases can modulate RET function and signaling remain largely unexplored. In this study, oligopeptide arrays were used to screen substrates directly phosphorylated by purified recombinant wild-type and oncogenic RET kinase domain in the presence or absence of small molecule inhibitors. The results of the peptide array were validated by enzyme kinetics, in vitro kinase, and cell-based experiments. The identification of focal adhesion kinase (FAK) as a direct substrate for RET kinase revealed (i) a RET-FAK transactivation mechanism consisting of direct phosphorylation of FAK Tyr-576/577 by RET and a reciprocal phosphorylation of RET by FAK, which crucially is able to rescue the kinase-impaired RET K758M mutant and (ii) that FAK binds RET via its FERM domain. Interestingly, this interaction is abolished upon RET phosphorylation, indicating that RET binding to the FERM domain of FAK is a priming step for RET-FAK transactivation. Finally, our data indicate that FAK inhibitors could be used as potential therapeutic agents for patients with multiple endocrine neoplasia type 2 tumors because both, treatment with the FAK kinase inhibitor NVP-TAE226 and FAK down-regulation by siRNA reduced RET phosphorylation and signaling as well as the proliferation and survival of tumor and transfected cell lines expressing oncogenic RET.

Description

NVP-TAE 226 (TAE226) is a potent and ATP-competitive dual FAK and IGF-1R inhibitor with IC50s of 5.5 nM and 140 nM, respectively. NVP-TAE 226 (TAE226) also effectively inhibits Pyk2 and insulin receptor (InsR) with IC50s of 3.5 nM and 44 nM, respectively.

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