OSU-03012 (AR-12) 化学構造
分子量: 460.45

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Quality Control & MSDS

製品情報

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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
Solubility 0.5% methylcellulose/0.2% Tween 80 30 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.

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

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
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 OSU-03012 (AR-12) SDF
分子量 460.45
化学式

C26H19F3N4O

CAS No. 742112-33-0
保管 2年-20℃
6月-80℃in solvent (DMSO, water, etc.)
別名
溶解度 (25°C) * In vitro DMSO 11 mg/mL (23.88 mM)
<1 mg/mL (<1 mM)
エタノール <1 mg/mL (<1 mM)
In vivo 0.5% methylcellulose/0.2% 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 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 (3)


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Rating
Source J Biol Chem, 2014, 289(38), 26155-66. OSU-03012 (AR-12) purchased from Selleck
Method Western blot
Cell Lines HEK293-AT1A cells
Concentrations 10 uM
Incubation Time 6 h
Results It shows the effects of PD98059 and OSU03012 on basal Akt phosphorylation in HEK293-AT1A cells. As expected, no significant change in total cellular phospho-Akt was measurable in response to AngII or SII exposure. Importantly, while the PDK1 inhibitor, OSU03012, dramatically reduced global Akt phosphorylation, the MEK1/2 inhibitor PD98059 had no effect, demonstrating that it did not nonspecifically affect Akt activity at the concentration employed.

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Rating
Source PLoS One, 2013, 8, 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).

Click to enlarge
Rating
Source Anticancer Drugs, 2013, 24(7), 690-8. OSU-03012 (AR-12) purchased from Selleck
Method TUNEL assay
Cell Lines Eca-109 cells
Concentrations 2 uM
Incubation Time 24 h
Results It investigated whether it could induce apoptosis in Eca-109 cells by the TUNEL assay. As shown, apoptotic cells were detected after 24 h of treatment with OSU-03012. Control Eca-109 cells showed 11.3±5% TUNEL-positive cells, whereas Eca-109 cells treated with 2 mmol/l OSU-03012 showed 56.9±2% TUNEL-positive cells.

製品表彰状 (8)

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