OSU-03012 (AR-12)

Catalog No.S1106

OSU-03012 (AR-12) is a potent inhibitor of recombinant PDK-1 with IC50 of 5 μM in a cell-free assay and 2-fold increase in potency over OSU-02067.

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OSU-03012 (AR-12) Chemical Structure

OSU-03012 (AR-12) Chemical Structure
Molecular Weight: 460.45

Validation & Quality Control

3 customer reviews :

Quality Control & MSDS

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Product Information

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Product Description

Biological Activity

Description OSU-03012 (AR-12) is a potent inhibitor of recombinant PDK-1 with IC50 of 5 μM in a cell-free assay and 2-fold increase in potency over OSU-02067.
Targets PDK-1 [1]
(Cell-free assay)
IC50 5 μM
In vitro 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 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]
Features A derivative of celecoxib with 10-fold greater antitumor activity, but lacks celecoxib's COX-2 inhibitory activity.

Protocol(Only for Reference)

Kinase Assay: [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.

Cell Assay: [1]

Cell lines PC-3 cells
Concentrations 0-10 μM
Incubation Time ~72 hours
Method 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.

Animal Study: [4]

Animal Models Huh7 tumor xenografts in male BALB/c nude mice
Formulation Dissolved in 0.5% methylcellulose, 0.1% Tween 80
Dosages 100-200 mg/kg
Administration Daily by gavage

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

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
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

References

[1] Zhu J, et al. Cancer Res, 2004, 64(12), 4309-4318.

[2] Yacoub A, et al. Mol Pharmacol, 2006, 70(2), 589-603.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-06-18)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT00978523 Completed Solid Tumors|Lymphoma Arno Therapeutics August 2009 Phase 1

Chemical Information

Download OSU-03012 (AR-12) SDF
Molecular Weight (MW) 460.45
Formula

C26H19F3N4O

CAS No. 742112-33-0
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 11 mg/mL (23.88 mM)
Water <1 mg/mL (<1 mM)
Ethanol <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.
Chemical Name 2-amino-N-(4-(5-(phenanthren-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)acetamide

Customer Product Validation(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).

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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.

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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