TWS119 化学構造
分子量: 318.33

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製品説明

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製品の説明

生物活性

製品説明 TWS119は、30nMのIC50によるグリコーゲン・シンターゼ・キナーゼ-3β(GSK-3β)阻害剤です。
ターゲット GSK-3β
IC50 30 nM [1]
In vitro試験 Treatment of a monolayer of P19 cells with 1 μM TWS119 causes 30–40% cells to differentiate specifically into neuronal lineages based on counting of TuJ1 positive cells with correct neuronal morphology (up to 60% neuronal differentiation occurred through the standard EB formation protocol with concomitant TWS119 treatment). TWS119 tightly binds to GSK-3β (K D = 126 nM) which is quantified by surface plasmon resonance (SPR) and further demonstrates an IC50 of 30 nM. [1] TWS119 is found to potently induces neuronal differentiation in both mouse embryonal carcinoma and ES cells. [2] TWS119 treatment towards hepatic stellate cells (HSC) leads to reduced b-catenin phosphorylation, induces nuclear translocation of b-catenin, elevates glutamine synthetase production, impedes synthesis of smooth muscle actin and Wnt5a, but promotes the expression of glial fibrillary acidic protein, Wnt10b, and paired-like homeodomain transcription factor 2c. [3] TWS119 triggers a rapid accumulation of β-catenin (mean 6.8 -fold increase by densitometry), augments nuclear protein interaction with oligonucleotide containing the DNA sequences to which Tcf and Lef bind and sharply up-regulates the expression of Tcf7, Lef1 and other Wnt target genes including Jun, Ezd7 (encoding Frizzled-7), Nlk (encoding Nemo-like kinase). TWS119 induces a dose-dependent decrease in T cell-specific killing and IFN-g release associated with the preservation of the ability to produce IL-2. [4] A recent study indicates Wnt signaling is induced in polyclonally activated human T cells by treatment with TWS119. These T cells preserve a native CD45RA(+)CD62L(+) phenotype compared with control-activated T cells that progresses to a CD45RO(+)CD62L(-) effector phenotype and this occurs in a TWS119 dose-dependent manner. TWS119-induced Wnt signaling reduces T cell expansion as a result of a block in cell division, and impairs acquisition of T cell effector function as measured by degranulation and IFN-γ production in response to T cell activation. The block in T cell division may be attributed to reduced IL-2Rα expression in TWS119-treated T cells that lowers their capacity to use autocrine IL-2 for expansion. [5]
In vivo試験 A cell population that expressed low levels of CD44 and high levels of CD62L on the cell surface when 30 mg/kg of TWS119 is administered. [4]
臨床試験
特集

プロトコル (参考用のみ)

キナーゼアッセイ: [1]

Surface Plasmon Resonance (SPR) SPR measurement sare performed on a BIAcore S51 instrument at 25 °C in PBS buffer. Relative light units (11,000–17,000) of a GSK-3β-GST fusion protein are immobilized on S series CM5 biosensor chips by EDC [1-ethyl-3-(3-dimethylaminopropyl)carbodiimide] coupling procedures. Briefly, GSK-3βis diluted into mildly acidic buffer (10 mM KAc, pH 5.0) and injected for 7 minutes at concentrations of 20–200 μg/ml onto a sensor chip previously activated by a 7-min incubation with a 1:1 mixture of EDC (0.2 M) and N-hydroxysuccinimide (NHS, 0.05 M). Finally, unreacted sites of the biosensor matrix are blocked by a 7-min injection of ethanolamine (1 M, pH 8.5). Subsequently, TWS119 is injected for 90 seconds at increasing concentrations (0, 2, 4, 8, 16, 32, 62.5, 125, 250, 500, and 1,000 nM), and dissociation of GSK-3β-TWS119 complexes is followed for 300 seconds. Evaluation of SPR data is performed by using the S51 evaluation software package. Data from two independent titration experiments performed on four different surfaces are averaged. A 1:1 binding model is assumed for the determination of thermodynamic and kinetic binding constants.

動物実験: [4]

動物モデル Pmel-1 TCR-transgenic mice and pmel-1 ly5.1 double-transgenic mice and pmel-1 Thy1.1 double-transgenic mice
製剤 TWS119 is dissolved in DMSO.
投薬量 30 mg/kg
投与方法 Intraperitoneal injection

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

参考

化学情報

Download TWS119 SDF
分子量 318.33
化学式

C18H14N4O2

CAS No. 601514-19-6
保管 2年-20℃
6月-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 64 mg/mL (201.04 mM)
<1 mg/mL (<1 mM)
エタノール <1 mg/mL (<1 mM)
In vivo 1% DMSO/30% polyethylene glycol/1% Tween 80 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
化学名 3-(6-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenol

カスタマーフィードバック (2)


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Source Int J Biochem Cell Biol, 2013, 45(9), 2066-75. TWS119 purchased from Selleck
Method Western blot analysis/ GSK-3β kinase activity assay/ Immunofluorescence
Cell Lines HKC cells
Concentrations 10 μM
Incubation Time 24 h
Results TWS119 was used to explore the direct effect of GSK-3 activity on SREBP-1 expression and lipid metabolism in HKC cells. We treated HKC cells with 10 μM TWS119 and the results demonstrated that it effectively suppressed the activity of GSK-3 via the GSK-3 kinase assay (Fig. 6A). In addition, compared with those of the normal control cells, the levels of SREBP-1 and ADRP were increased in the TWS119-treated HKC cells, as shown in Fig. B and C.

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Source PLoS One, 2014, 9(7), e100947. TWS119 purchased from Selleck
Method Western blot analysis
Cell Lines HCT116p53KO cells
Concentrations 2 mM
Incubation Time 24 h
Results GSK3 activity is usually kept off by an inhibitory phosphorylation on Ser (S21 for GSK3A and S9 for GSK3B) that has to be removed to allow phosphorylation on Tyr (T279 for GSK3A and T216 for GSK3B), and therefore enzymatic activation. At variance, very low concentrations of inhibitors-such as BIO and TWS119 - despite increasing the levels of phospho-S21, but not phospho-S9, abolished both T276 and T216 phosphorylation, indicating that these inhibitors affect the activity of both isoforms, perhaps to a different extent.

文献中の引用 (4)

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description
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