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
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
別名 N/A
溶解度 (25°C)
  • DMSO 3 mg/mL
  • 水 <1 mg/mL
  • エタノール <1 mg/mL
保管 2年 -20°C
6月-80°Cin DMSO
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).

製品表彰状 (10)

  • Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. [Wilson TR, et al. Nature 2012;487(7408):505-9]

    PubMed: 22763448
  • MED12 controls the response to multiple cancer drugs through regulation of TGF-β receptor signaling. [Huang S, et al. Cell 2012;151(5):937-50]

    PubMed: 23178117
  • Using tandem mass spectrometry in targeted mode to identify activators of class IA PI3K in cancer. [Yang X, et al. Cancer Res 2011;71(18):5965-75]

    PubMed: 21775521
  • Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinase inhibitors. [Lovly CM, et al. Cancer Res 2011;71(14):4920-31]

    PubMed: 21613408
  • Identifying and targeting ROS1 gene fusions in non-small cell lung cancer. [Davies KD, et al. Clin Cancer Res 2012;18(17):4570-9]

    PubMed: 22919003
  • Paracrine receptor activation by microenvironment triggers bypass survival signals and ALK inhibitor resistance in EML4-ALK lung cancer cells. [Yamada T, et al. Clin Cancer Res 2013;18(13):3592-602]

    PubMed: 22553343
  • Epithelial-mesenchymal transition leads to crizotinib resistance in H2228 lung cancer cells with EML4-ALK translocation. [Hyeong Ryul Kim, et al. MOLECULAR ONCOLOGY 2013;7(6):1093-102]

    PubMed: 23993685
  • Identification of oncogenic point mutations and hyperphosphorylation of anaplastic lymphoma kinase in lung cancer. [Wang YW, et al. Neoplasia 2011;13(8):704-15]

    PubMed: 21847362
  • Interferon-γ induces leucine-rich repeat kinase LRRK2 via extracellular signal-regulated kinase ERK5 in macrophages. [Kuss M, et al. J Neurochem 2014;10.1111/jnc.12668]

    PubMed: 24479685
  • Epithelial-mesenchymal transition confers resistance to FGFR inhibitors in gastric cancer cell line [Paulina Grygielewicz, et al. CELON PHARMA 2013;2013]

技術サポート&よくある質問(FAQ)

顧客がするかもしれない質問に対する答えは、指示を取り扱っている阻害剤で見つかります。話題は、貯蔵液(阻害剤と特別な注意を細胞ベースの分析法と動物のために必要とする問題を保存することは実験します)を準備する方法を含みます。

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