Original: OSU-03012 742112-33-0, stock more than 100g

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Description: 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-centereName: OSU-03012 

CAS#: 742112-33-0 (free base) 

Chemical Formula: C26H19F3N4O 

Exact Mass: 460.1511 

Molecular Weight: 460.45 

Elemental Analysis: C, 67.82; H, 4.16; F, 12.38; N, 12.17; O, 3.47

Related CAS #: 742112-33-0 (free base)   471979-81-3 (HCl)    

Synonym: AR12; AR-12; AR 12; OSU03012; OSU-03012; OSU 03012.

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

InChi Key: YULUCECVQOCQFQ-UHFFFAOYSA-N

InChi Code: 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)

SMILES Code: O=C(NC1=CC=C(N2N=C(C(F)(F)F)C=C2C3=CC=C4C5=CC=CC=C5C=CC4=C3)C=C1)CNd Phase I clinical study of AR-12 in adult patients with advanced or recurrent solid tumors or lymphoma.

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: soluble in DMSO, not soluble in water.

Shelf Life: >5 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

Harmonized System Code: 293490

ADDITIONAL INFORMATION

Related: 

742112-33-0(AR-12) 

1471979-81-3 (AR-12 Hydrochloride)

AR-12 (formerly known as OSU-03012) is a potentially first-in-class, orally available, targeted anti-cancer agent that inhibits PDK-1, a protein in the PI3K/Akt pathway, and also causes cell death through the induction of endoplasmic reticulum (ER) stress. Arno is currently enrolling patients with advanced or recurrent solid tumors or lymphoma in a Phase I clinical study. Preclinical data have demonstrated that AR-12 has activity in a wide range of tumor types and sas both a single agent and in combination with several widely used anti-cancer agents including Avastin®, Herceptin®, Gleevec®, Tarceva®, Sorafinib®, Nexavar®, and tamoxifen. 

  

OSU-03012 is a derivative of celecoxib with anticancer activity. The mechanism of action is presumably 3-phosphoinositide-dependent kinase 1 (PDK1) inhibition.  OSU-03012 inhibited cell growth of Huh7, Hep3B, and HepG2 cells with IC(50) below 1 mumol/L. In Huh7 cells, OSU-03012 did not suppress PDK1 or AKT activity. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay and flow cytometry analysis indicated that OSU-03012 did not induce cellular apoptosis. Instead, morphologic studies by light and electron microscopy, as well as special biological staining with monodansylcadaverine, acridine orange, and microtubule-associated protein 1 light chain 3, revealed OSU-03012-induced autophagy of Huh7 cells. This OSU-03012-induced autophagy was inhibited by 3-methyladenine. Moreover, reactive oxygen species (ROS) accumulation was detected after OSU-03012 treatment. Blocking ROS accumulation with ROS scavengers inhibited autophagy formation, indicating that ROS accumulation and subsequent autophagy formation might be a major mechanism of action of OSU-03012. Daily oral treatment of BALB/c nude mice with OSU-03012 suppressed the growth of Huh7 tumor xenografts. Electron microscopic observation indicated that OSU-03012 induced autophagy in vivo. Together, our results show that OSU-03012 induces autophagic cell death but not apoptosis in HCC and that the autophagy-inducing activity is at least partially related to ROS accumulation.( source: Cancer Res. 2008 Nov 15;68(22):9348-57., or http://www.ncbi.nlm.nih.gov/pubmed/19010909). 

    

  

REFERENCES

1: Kuo WW, Weng JR, Huang CY, Tsai CH, Liu WH, Wen CH, Tsai SC, Wu CH. Exploring the molecular mechanisms of OSU-03012 on vascular smooth muscle cell proliferation. Mol Cell Biochem. 2010 Jul 13. [Epub ahead of print] PubMed PMID: 20625798.

2: Hamed HA, Yacoub A, Park MA, Eulitt P, Sarkar D, Dimitriev IP, Chen CS, Grant S, Curiel DT, Fisher PB, Dent P. OSU-03012 enhances Ad.mda-7-induced GBM cell killing via ER stress and autophagy and by decreasing expression of mitochondrial protective proteins. Cancer Biol Ther. 2010 Apr 4;9(7). [Epub ahead of print] PubMed PMID: 20107314; PubMed Central PMCID: PMC2888700.

3: Bai LY, Weng JR, Tsai CH, Sargeant A, Lin CW, Chiu CF. OSU-03012 sensitizes TIB-196 myeloma cells to imatinib mesylate via AMP-activated protein kinase and STAT3 pathways. Leuk Res. 2010 Jun;34(6):816-20. Epub 2009 Dec 14. PubMed PMID: 20006997.

4: Chiu HC, Soni S, Kulp SK, Curry H, Wang D, Gunn JS, Schlesinger LS, Chen CS. Eradication of intracellular Francisella tularensis in THP-1 human macrophages with a novel autophagy inducing agent. J Biomed Sci. 2009 Dec 9;16:110. PubMed PMID: 20003180; PubMed Central PMCID: PMC2801672.

5: Ghavami S, Hashemi M, Ande SR, Yeganeh B, Xiao W, Eshraghi M, Bus CJ, Kadkhoda K, Wiechec E, Halayko AJ, Los M. Apoptosis and cancer: mutations within caspase genes. J Med Genet. 2009 Aug;46(8):497-510. Epub 2009 Jun 7. Review. PubMed PMID: 19505876.

6: Lee TX, Packer MD, Huang J, Akhmametyeva EM, Kulp SK, Chen CS, Giovannini M, Jacob A, Welling DB, Chang LS. Growth inhibitory and anti-tumour activities of OSU-03012, a novel PDK-1 inhibitor, on vestibular schwannoma and malignant schwannoma cells. Eur J Cancer. 2009 Jun;45(9):1709-20. Epub 2009 Apr 7. PubMed PMID: 19359162; PubMed Central PMCID: PMC2692816.

7: Gao M, Yeh PY, Lu YS, Hsu CH, Chen KF, Lee WC, Feng WC, Chen CS, Kuo ML, Cheng AL. OSU-03012, a novel celecoxib derivative, induces reactive oxygen species-related autophagy in hepatocellular carcinoma. Cancer Res. 2008 Nov 15;68(22):9348-57. PubMed PMID: 19010909.

8: Ding H, Han C, Guo D, Wang D, Duan W, Chen CS, D'Ambrosio SM. Sensitivity to the non-COX inhibiting celecoxib derivative, OSU03012, is p21(WAF1/CIP1) dependent. Int J Cancer. 2008 Dec 15;123(12):2931-8. PubMed PMID: 18798266; PubMed Central PMCID: PMC2605165.

9: Ding H, Han C, Guo D, Wang D, Chen CS, D'Ambrosio SM. OSU03012 activates Erk1/2 and Cdks leading to the accumulation of cells in the S-phase and apoptosis. Int J Cancer. 2008 Dec 15;123(12):2923-30. PubMed PMID: 18798257.

10: Weng SC, Kashida Y, Kulp SK, Wang D, Brueggemeier RW, Shapiro CL, Chen CS. Sensitizing estrogen receptor-negative breast cancer cells to tamoxifen with OSU-03012, a novel celecoxib-derived phosphoinositide-dependent protein kinase-1/Akt signaling inhibitor. Mol Cancer Ther. 2008 Apr;7(4):800-8. PubMed PMID: 18413793.