Molecular Weight(MW): 460.45
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.
Cited by 13 Publications
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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.
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|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.|
|Features||A derivative of celecoxib with 10-fold greater antitumor activity, but lacks celecoxib's COX-2 inhibitory activity.|
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.  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.  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.  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.  A recent study shows that OSU-03012 could enhance the susceptibility of (Bcr)-Abl mutant cell lines to imatinib-induced apoptosis. 
|In vivo||OSU-03012 suppresses tumor growth by 57.59% and increases cleaved LC3 in Huh7 tumor xenografts at 200 mg/kg.  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.  OSU-03012 is well tolerated and inhibits the growth of HMS-97 schwannoma xenografts by 55% after oral administration. |
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.
-  Zhu J, et al. Cancer Res, 2004, 64(12), 4309-4318.
-  Yacoub A, et al. Mol Pharmacol, 2006, 70(2), 589-603.
-  Porchia LM, et al. Mol Pharmacol, 2007, 72(5), 1124-1131.
|In vitro||DMSO||11 mg/mL (23.88 mM)|
|In vivo||0.5% methylcellulose+0.2% Tween 80||30 mg/mL|
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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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