OSU-03012 (AR-12) 化学構造
分子量: 460.45

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製品情報

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  • 研究分野

製品の説明

生物活性

情報 OSU-03012 (AR-12)は有効的に再編PDK-1を抑制、IC50が5µMになる。
目標 PDK-1
IC50 5 μM [1]
In vitro試験 OSU-03012 induces apoptotic death in PC-3 cells with IC50 of 5 µM and reduces the activity of immunoprecipitated p70S6K. OSU-03012 completely suppress cell growth in a diverse range of tumor cell lines at concentrations of 3–5 μm, as compared with the concentration of at least 50 μm required for celecoxib. [1] OSU-03012 promotes cell killing to a greater extent in glioma cells than in nontransformed astrocytes. OSU-03012 causes a dose-dependent induction of cell death that is not altered by p53 mutation, expression of ERBB1 VIII, or loss of phosphatase and tensin function due to a homolog deletion on chromosome 10. OSU-03012 and ionizing radiation cause an additive, caspase-independent elevation in cell killing. OSU-03012 lethality as a single agent or when combined with signaling modulators is not modified in cells lacking expression of BIM or of BAX/BAK. OSU-03012 promotes the release of cathepsin B from the lysosomal compartment and that of AIF from mitochondria. The lethality of OSU-03012 is attenuated in protein kinase R-like endoplasmic reticulum kinase-/- cells, which correlated with the reduced cleavage of BID and suppression of cathepsin B and AIF release into the cytosol. [2] OSU-03012 inhibits thyroid cancer cell (NPA, WRO, and ARO cells) proliferation, migration and induces apoptosis, which results in an increase of cells in the S phase without an increase of cells in G2. OSU-03012 is an ATP-competitive inhibitor of PAK activity and suppresses the phosphorylation of AKT in thyroid cancer cells. [3] OSU-03012 inhibits cell growth of hepatocellular carcinoma cell lines including Huh7, Hep3B and HepG2 cells with IC50 values below 1 μM. OSU-03012 does not suppress PDK1 or AKT activity or induce cellular apoptosis but induces autophagy in Huh7 cells. Moreover, accumulation of reactive oxygen species (ROS) is detected after OSU-03012 treatment. [4] A recent study shows that OSU-03012 could enhance the susceptibility of (Bcr)-Abl mutant cell lines to imatinib-induced apoptosis. [5]
In vivo試験 OSU-03012 suppresses tumor growth by 57.59% and increases cleaved LC3 in Huh7 tumor xenografts at 200 mg/kg. [4] OSU-03012 remarkably decreases expression of EGFR protein in the tumors by 48% compared with vehicle controls and also prevents YB-1 from binding to the EGFR promoter in MDA-MB-435/LCC6 xenografts. [6] OSU-03012 is well tolerated and inhibits the growth of HMS-97 schwannoma xenografts by 55% after oral administration. [7]
臨床試験
特集 A derivative of celecoxib with 10-fold greater antitumor activity, but lacks celecoxib's COX-2 inhibitory activity.

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]

PDK-1 Kinase Assay This in vitro assay is performed using a PDK-1 kinase assay kit. This cell-free assay is based on the ability of recombinant PDK-1, in the presence of DMSO vehicle or OSU-03012, to activate its downstream serum- and glucocorticoid-regulated kinase which, in turn, phosphorylates the Akt/serum- and glucocorticoid-regulated kinase-specific peptide substrate RPRAATF with [γ-32P]ATP. The 32P-phosphorylated peptide substrate is then separated from the residual [γ-32P]-ATP by using P81 phosphocellulose paper and quantitated in a scintillation counter after three washes with 0.75% phosphoric acid.

細胞アッセイ: [1]

細胞系 PC-3 cells
濃度 0-10 μM
処理時間 ~72 hours
方法 The effect of OSU-03012 on PC-3 cell viability is assessed by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay in six replicates. Cells are grown in 10% FBS- supplemented RPMI 1640 in 96-well, flat-bottomed plates for 24 hours. They are exposed to various concentrations of OSU-03012 (0-10 μM) dissolved in DMSO (final concentration ≤0.1%) in 1% serum-containing RPMI 1640 for different time intervals (~72 hours). Controls receive DMSO vehicle at a concentration equal to that in OSU-03012-treated cells. The medium is removed and replaced by 200 μL of 0.5 mg/mL 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide in 10% FBS-containing RPMI 1640. The cells are incubated in the CO2 incubator at 37 °C for 2 hours. Supernatants are removed from the wells, and the reduced 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide dye is solubilized in 200 μL DMSO per well. Absorbance at 570 nm is determined by using a plate reader.

動物実験: [4]

動物モデル Huh7 tumor xenografts in male BALB/c nude mice
製剤 Dissolved in 0.5% methylcellulose, 0.1% Tween 80
投薬量 100-200 mg/kg
管理 Daily by gavage
1

参考

化学情報

Download OSU-03012 (AR-12) SDF
分子量 460.45
化学式

C26H19F3N4O

CAS No. 742112-33-0
別名 N/AAR-12
溶解度 (25°C)
  • DMSO 11 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 2-amino-N-(4-(5-(phenanthren-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)acetamide

研究分野

カスタマーレビュー (1)


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Source , , PLoS One, 2013, 8(9):e75100 . OSU-03012 (AR-12) purchased from Selleck
Method Western blot
Cell Lines Orbital fibroblasts
Concentrations 5 uM
Incubation Time 6 h
Results The siRNA targeting PDK1 attenuates TSH-dependent PKCm Ser 916 phosphorylation in fibroblasts (Fig. C) while the PDK1 inhibitor, OSU-03012 (5 mM) [54] blocks TSH-dependent phosphorylation of PKCm Ser 916 and PKCbII Ser 660 levels in the respective cell-types (Fig. C). The inhibitor also reduces levels of TSH-dependent pAKT Threonine 308 in fibroblasts but fails to do so in fibrocytes (Fig. D, 14.461.2% and 2.560.6%, respectively).

製品表彰状 (4)

  • Thyrotropin Regulates IL-6 Expression in CD34+ Fibrocytes: Clear Delineation of Its cAMP-Independent Actions. [Raychaudhuri N, et al. PLoS One 2013;8(9):e75100]

    PubMed: 24086448
  • Endogenous adenosine contributes to renal sympathetic neurotransmission via postjunctional A1 receptor-mediated coincident signaling. [Edwin K, et al. Am J Physiol Renal Physiol 2011;302(4):F466-76]

    PubMed: 22114202
  • Cryptococcus neoformans Phosphoinositide-Dependent Kinase 1 (PDK1) Ortholog Is Required for Stress Tolerance and Survival in Murine Phagocytes. [Chabrier-Roselló Y, et al. Eukaryot Cell 2012;12(1):12-22]

    PubMed: 23087368
  • OSU-03012, a non-cox inhibiting celecoxib derivative, induces apoptosis of human esophageal carcinoma cells through a p53/Bax/cytochrome c/caspase-9-dependent pathway. [Liu J, et al. Anticancer Drugs 2013;24(7):690-8]

    PubMed: 23652278

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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