OSU-03012 (AR-12)

Catalog No.S1106

OSU-03012 (AR-12) Chemical Structure

Molecular Weight(MW): 460.45

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

Size Price Stock Quantity  
In DMSO USD 130 In stock
USD 70 In stock
USD 220 In stock
USD 670 In stock
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3 Customer Reviews

  • Serum-deprived HEK293-AT1A cells were pretreated with PD98059 (20 uM; 1 h) or OSU03012 (10 uM; 6 h) prior to 5 min stimulation with AngII (100 nm) or SII (50 uM). A, abundance of phospho-Akt T308 in whole cell detergent lysates. Representative phospho-Akt and total Akt immunoblots are shown above a bar graph depicting the mean ?S.E. of three biological replicates.

    J Biol Chem 2014 289(38), 26155-66. OSU-03012 (AR-12) purchased from Selleck.

    (C) Orbital fibroblasts, in this case from a patient with TAO, were transfected with PDK1siRNA while fibrocytes were treated with OSU-03012 (5 mM) for 6 h. Cultures were treated as indicated (bTSH, 5 mIU/mL) for 30 min. Cellular protein was subjected to Western blot analysis of PKCm and pPKCm in fibroblasts (left panel) and PKCbII and pPKCbII in fibrocytes (right panel). (D) Confluent cultures were pre-treated without or with OSU-03012 (5 mM) for 6 h, then treated with nothing (control) or bTSH (5 mIU/ml) for 30 min. Cellular proteins were subjected to Western blot analysis probing with AKT and pAKT antibodies. Inhibition of TSH-dependent pAKT by OSU-03012 in 3 separate experiments was 14.461.2% and 2.560.6% in fibroblasts and fibrocytes, respectively.

    PLoS One 2013 8, e75100. OSU-03012 (AR-12) purchased from Selleck.

  • Apoptosis is detectable in OSU-03012-treated Eca-109 cells. After treatment with or without 2 umol/l OSU-03012 for 24 h, Eca-109 cells were fixed for the TUNEL assay ( x 200).

    Anticancer Drugs 2013 24(7), 690-8. OSU-03012 (AR-12) purchased from Selleck.

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Biological Activity

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

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
mouse RAW264.7 cells M3\0dGZ2dmO2aX;uJIF{e2G7 MWW4JIg> NYK1VZQ2SW62aX3pZ5Jw[mmjbDDhZ5Rqfmm2eTDh[4FqdnO2IGPhcI1wdmWubHGg[Y51\XKrY3Ggd4Vzd3[jcjDUfZBpcW23cnn1cUBCXEOFIEG0NFI5KGmwZnXjeIVlKGmwIH3veZNmKFKDV{K2OE44KGOnbHzzJIF{e2W|c3XkJIF{KGmwaHnibZRqd25ib3[gbY51emGlZXzseYxieiCkYXP0[ZJq[WxiZ4Lve5RpKGGodHXyJFghcHK|LDDJR|UxRTBwMjFOwG0> MUGxPVgxPTV4OB?=
mouse RAW264.7 cells MXnDfZRwfG:6aXRCpIF{e2G7 NWfjVW1UOjRiaB?= MXPDfZRwfG:6aXPpeJkh[WejaX7zeEBud3W|ZTDSRXczPjRwNzDj[YxteyCjc4Pld5Nm\CCjczDj[YxtKH[rYXLpcIl1gSCjZoTldkAzPCCqcoOgZpkhVVSWIHHzd4F6NCCLQ{WwQVExKM7:TR?= MX2xPVgxPTV4OB?=

... Click to View More Cell Line Experimental Data

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]

Protocol

Kinase Assay:[1]
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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 Research:[1]
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  • 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.
    (Only for Reference)
Animal Research:[4]
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  • 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
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 11 mg/mL (23.88 mM)
Water slightly soluble or insoluble
Ethanol slightly soluble or insoluble
In vivo Add solvents individually and in order:
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.

Chemical Information

Molecular Weight 460.45
Formula

C26H19F3N4O

CAS No. 742112-33-0
Storage powder
in solvent
Synonyms N/A

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Clinical Trial Information

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

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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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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID