OSU-03012

OSU03012; also known as AR12, is an orally available, targeted anti-cancer agent that has been shown in pre-clinical studies to inhibit PDK-1, a protein in the PI3K/Akt pathway that is involved in the growth and proliferation of cells, including cancer cells. AR-12 may also cause cell death through the induction of stress in the endoplasmic reticulum. We are currently conducting a multi-centered Phase I clinical study of AR-12 in adult patients with advanced or recurrent solid tumors or lymphoma.

Product information

CAS Number: 742112-33-0

Molecular Weight: 460.45

Formula: C26H19F3N4O

Synonym:

AR12

AR-12

AR 12

OSU03012

OSU 03012

Related CAS Number:

1471979-81-3 (OSU-03012 hydrochloride)

Chemical Name: 2-amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenyl} acetamide

Smiles: NCC(=O)NC1C=CC(=CC=1)N1N=C(C=C1C1=CC2=CC=C3C=CC=CC3=C2C=C1)C(F)(F)F

InChiKey: YULUCECVQOCQFQ-UHFFFAOYSA-N

InChi: InChI=1S/C26H19F3N4O/c27-26(28,29)24-14-23(33(32-24)20-10-8-19(9-11-20)31-25(34)15-30)18-7-12-22-17(13-18)6-5-16-3-1-2-4-21(16)22/h1-14H,15,30H2,(H,31,34)

Technical Data

Appearance: Solid Power

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: DMSO: 11 mg/mL(23.88 mM). Water: Insoluble.

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥12 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined

HS Tariff Code: 382200

How to use

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. 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.

References:

1. Porchia LM, et al. Mol Pharmacol, 2007, 72(5), 1124-1131.
2. Yacoub A, et al. Mol Pharmacol, 2006, 70(2), 589-603.
3. Zhu J, et al. Cancer Res, 2004, 64(12), 4309-4318.

Products are for research use only. Not for human use.