OSU-03012 (AR-12) 742112-33-0

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Molecular Weight: 460.45 OSU-03012 is a Potent Inhibitor of recombinant PDK-1 with IC50 of 5 μM and 2-fold increase in potency over OSU-02067.


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.






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.






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
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)

Species	Baboon	Dog	Monkey	Rabbit	Guinea pig	Rat	Hamster	Mouse
Weight (kg)	12	10	3	1.8	0.4	0.15	0.08	0.02
Body Surface Area (m2)	0.6	0.5	0.24	0.15	0.05	0.025	0.02	0.007
Km factor	20	20	12	12	8	6	5	3

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)

Chemical Information

Molecular Weight (MW)	460.45
Formula	C26H19F3N4O
CAS No.	742112-33-0

Storage	3 years -20℃Powder
	6 months-80℃in solvent (DMSO, water, etc.)
Synonyms

Solubility (25°C) *	In vitro	DMSO	11 mg/mL (23.88 mM)
		Water	<1 mg/mL (
		Ethanol	<1 mg/mL (
	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

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Product Categories : PI3K/Akt/mTOR > PDK-1 Inhibitor