TAE226 (also known as NVP-TAE226; TAE-226) is a novel, potent, selective and ATP competitive small molecule FAK (focal adhesion kinase) inhibitor with potential antineoplastic activity. It inhibits FAK with IC50 of 5.5 nM, shows modest potency against other kinases such as Pyk2, InsR, IGF-1R, ALK, and c-Met. TAE 226 demonstrate significant in vivo antitumor efficacy in Nude mice (male) bearing intracranial glioma xenografts. 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).

Physicochemical Properties

Molecular Formula	C23H25CLN6O3
Molecular Weight	468.94
Exact Mass	468.167
CAS #	761437-28-9
Related CAS #	761437-28-9
PubChem CID	9934347
Appearance	White to khaki solid powder
Density	1.3±0.1 g/cm3
Index of Refraction	1.659
LogP	2.35
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	8
Rotatable Bond Count	7
Heavy Atom Count	33
Complexity	625
Defined Atom Stereocenter Count	0
InChi Key	UYJNQQDJUOUFQJ-UHFFFAOYSA-N
InChi Code	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)
Chemical Name	2-((5-chloro-2-((2-methoxy-4-morpholinophenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide
Synonyms	TAE-226, TAE226, TAE 226, NVP-TAE226, NVPTAE226, NVP TAE226,
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

ln Vitro	Strong ATP competitive inhibitor NVP-TAE 226 (TAE226) inhibits several tyrosine protein kinases, particularly FAK and IGF-IR kinases. FAK, IGF-IR kinase, and IR kinase were inhibited in a cell-based kinase experiment with IC50s ranging from 100 to 300 nM. This was less sensitive than the other kinases examined, all of which had IC50s that were ten times higher. NVP-TAE 226 prevents FAK from becoming autophosphorylated in culture due to extracellular matrix (Tyr395). Additionally, IGF-I-induced phosphorylation of IGF-IR and the activity of its downstream target genes (including Akt and MAPK) are inhibited by NVP-TAE 226. NVP-TAE 226 attenuates G2-M cell cycle progression associated with decreased cyclin B1 and phosphorylated cdc2 (Tyr15) protein expression, and slows tumor cell development (measured by cell viability assay). Tumor cell invasion in the in vitro Matrigel invasion experiment was at least 50% reduced by NVP-TAE 226 treatment in comparison to the control. It's interesting to note that tumor cells with wild-type p53 exhibit primarily G2-M arrest upon TAE226 treatment, but tumor cells with mutant p53 experience apoptosis [1].
ln Vivo	The median survival of U87 tumor xenograft rats was extended by 6 and 7 days, respectively, upon treatment with 50 or 75 mg/kg NVP-TAE 226 (TAE226) (P=0.084 and 7 days, respectively, in comparison to animals treated with a control group). P is equal to 0.042). On the other hand, the treatment of LN229 tumor xenograft animals with NVP-TAE 226 markedly increased their median survival time by 19 days (P<0.004 for both doses when compared to animals treated with vehicle) [1].
Animal Protocol	Dissolved in 0.5% methylcellulose; 75 mg/kg; Oral gavage Nude mice (male) bearing intracranial glioma xenografts
References	[1]. 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]. Laminin α2-mediated focal adhesion kinase activation triggers Alport glomerular pathogenesis. PLoS One. 2014 Jun 10;9(6):e99083. [3]. Crystal structures of the FAK kinase in complex with TAE226 and related bis-anilino pyrimidine inhibitors reveal a helical DFG conformation. PLoS One. 2008;3(11):e3800.
Additional Infomation	2-[[5-chloro-2-[2-methoxy-4-(4-morpholinyl)anilino]-4-pyrimidinyl]amino]-N-methylbenzamide is a member of morpholines.

Solubility Data

Solubility (In Vitro)

DMSO: 94 mg/mL (200.5 mM) Water:<1 mg/mL Ethanol:<1 mg/mL

Solubility (In Vivo)

Solubility in Formulation 1: 1.11 mg/mL (2.37 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 11.1 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 1.11 mg/mL (2.37 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 11.1 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 3: 0.5% methylcellulose:30 mg/mL  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.1325 mL	10.6623 mL	21.3247 mL
	5 mM	0.4265 mL	2.1325 mL	4.2649 mL
	10 mM	0.2132 mL	1.0662 mL	2.1325 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.