TAE684 (NVP-TAE684)

TAE684 (NVP-TAE684)は、3nMのIC50による強力で選択的なALKキナーゼ阻害剤です。

目録号S1108
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TAE684 (NVP-TAE684) 化学構造
分子量: 614.2

品質と確認

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Quality Control & MSDS

製品情報

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  • 研究分野
  • TAE684 (NVP-TAE684)のメカニズム

製品の説明

生物活性

情報 TAE684 (NVP-TAE684)は、3nMのIC50による強力で選択的なALKキナーゼ阻害剤です。
目標 ALK
IC50 3 nM [1]
In vitro試験 TAE684 does not exhibit significant cross-reactivity against other kinases. TAE684 potently inhibits the proliferation of Ba/F3 NPM-ALK cells with IC50 of 3 nM, without affecting the survival of Ba/F3 cells even at 1 μM. TAE684 also inhibits proliferation of NPM-ALK-expressing human ALCL cell lines including Karpas-299 and SU-DHL-1 with IC50 of 2–5 nM. Molecular modeling reveals that L258 may be one of the major kinase-selectivity determinants for TAE684. TAE684 treatment results in a rapid and sustained inhibition of phosphorylation of NPM-ALK. TAE684 induces apoptosis and G1 phase arrest in NPM-ALK-expressing Ba/F3 cells and ALCL patient cell lines. [1] TAE684 markedly overcomes Crizotinib-resistance in H3122 CR cells, harboring the fusion oncogene EML4-ALK, decreasing cell growth, suppressing ALK phosphorylation and inducing apoptosis.[2] Neurite outgrowth induced by expression of the mALK R1279Q mutant could be completely inhibited by TAE684 at 30 nM. [3]
In vivo試験 After 4 weeks of treatment with TAE684 at 3 and 10 mg/kg, there is a significant delay in lymphoma development and 100- to 1,000-fold reduction in luminescence signal, without any signs of compound- or disease-related toxicity in Karpas-299 lymphoma model. TAE684 treatment also induces disease regression in established Karpas-299 lymphomas and down-regulates CD30 expression. [1] TAE684 also shows impressive antitumor activity against H3122 CR xenograft tumors. [2] Furthermore, treatment with TAE684 improves the rough eye phenotype of both ALK mutants, especially that seen with ALKR1275Q, whereas Crizotinib has little effect on either phenotype. [3]
臨床試験
特集

推薦された実験操作 (公開の文献だけ)

キナーゼアッセイ: [1]

In vitro Enzyme Assays. All in vitro enzyme assays are done at Upstate Biotechnology with the exception of InsR and IGF-1R. To determine the IC50 of TAE684 against InsR and IGF-1R a homogeneous time-resolved fluorescence assay is performed. ATP (10 mM) and 20 mg/ml biotinylated PolyEY (Glu, Tyr 4:1) are combined with 50 nL of serial dilutions of TAE684 (10-500 nM) and 4 ng of InsR enzyme in the presence of the kinase reaction buffer (20 mM Tris譎Cl, pH 7.5/10 mM MgCl2/3 mM MnCl2/1 mM DTT/10 mM NaVO4/0.1 mg/ml of BSA). Assays are incubated for 1 hour at ambient temperature. Reactions are terminated by adding 10 mL of the detection solution containing 50 mM EDTA, 500 mM KF, 0.5 mg/ml of BSA, 5 mg/mL Eu3+ cryptate-labeled anti-phosphotyrosine antibody Mab PT66-K, and 5 mg/mL Streptavidin-XLent. The reaction is incubated for half an hour, and fluorescence signals are read on Analyst GT.

細胞アッセイ: [1]

細胞系 Luciferase-expressing Karpas-299, SU-DHL-1, and Ba/F3 cells and transformed Ba/F3 stably expressing NPM-ALK, Bcr-Abl, or TEL-kinase fusion constructs.
濃度 1 nM-10 μM
処理時間 2–3 days
方法 Cells are seeded in 384-well plates (2.5×104 cells per well) and incubated with serial dilutions of TAE684 or DMSO for 2–3 days. Luciferase expression is used as a measure of cell proliferation/survival and is evaluated with the Bright-Glo Luciferase Assay System. IC50 values are generated by using XLFit software.

動物実験: [1]

動物モデル Karpas-299 xenografts are established in 4- to 6-week old female Fox Chase SCIDBeige mice.
製剤 Resuspended in 10% 1-methyl-2-pyrrolidinone/90% polyethylene glycol 300 solution
投薬量 1, 3, and 10 mg/kg
管理 Once daily by oral gavage for 3 weeks
Solubility 30% PEG400/0.5% Tween80/5% propylene glycol, pH 4 10 mg/mL
* 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.
1

参考

化学情報

Download TAE684 (NVP-TAE684) SDF
分子量 614.2
化学式

C30H40ClN7O3S

CAS No. 761439-42-3
保管 2年-20℃
6月-80℃in DMSO
別名 N/A
溶解度 (25°C) * In vitro DMSO 3 mg/mL (4 mM)
<1 mg/mL (<1 mM)
エタノール <1 mg/mL (<1 mM)
In vivo 30% PEG400/0.5% Tween80/5% propylene glycol, pH 4 10 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 5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine

研究分野

カスタマーレビュー (4)


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Rating
Source Neoplasia Vol. 13, No. 8, 2011. TAE684 (NVP-TAE684) purchased from Selleck
Method Western blot
Cell Lines H-1299 cells
Concentrations 0.03-1uM
Incubation Time
Results Treatment efficiently inhibited the cell proliferation and phospho-Y1604 ALK expression of H694R or E1384K mutant ALK, but also to a degree higher than that of wild-type ALK.

Click to enlarge
Rating
Source Neoplasia Vol. 13, No. 8, 2011 . TAE684 (NVP-TAE684) purchased from Selleck
Method Xenograft
Cell Lines mice
Concentrations
Incubation Time 4 weeks
Results Consistently, TAE684 treatment repressed H694R- and E1384K-induced tumor growth compared with DMSO control.

Click to enlarge
Rating
Source Neoplasia Vol. 13, No. 8, 2011. TAE684 (NVP-TAE684) purchased from Selleck
Method Cell Proliferation Assay
Cell Lines H-1299 cells
Concentrations 0-3 uM
Incubation Time
Results Treatment efficiently inhibited the cell proliferation and phospho- Y1604 ALK expression of H694R or E1384K mutant ALK, but also to a degree higher than that of wild-type ALK.

Click to enlarge
Rating
Source Cancer Res , 2011, 71, 4920-31. TAE684 (NVP-TAE684) purchased from Selleck
Method Western blot
Cell Lines H3122 cells
Concentrations 100 nmol/L
Incubation Time 6 h
Results Figure A shows that the primary adaptors for PI3K activation are IRS1 and IRS2 in H3122 mouse xenografts. Interestingly, treatment with TAE-684 eliminates these interactions, suggesting that ALK signals to PI3K via IRS2 and IRS1. This is consistent with previous reports suggesting that NPM-ALK signals to PI3K via IRS proteins. The finding that IRS proteins were utilized to activate PI3K suggested that these cells might activate PI3K in response to IGF-I. Indeed, treatment of H3122 cells with IGF-I, but not EGF or HGF, rescued PI3K-AKT signaling with TAE-684 treatment (Fig. B).

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