AR-12 is a PI3-k/Akt pathway inhibitor that also possesses activity in the endoplasmic reticulum (ER) stress and other pathways targeting apoptosis. We are 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 shows promising activity in combination with several widely used anti-cancer agents including Avastin®, Herceptin®, Gleevec®, Tarceva®, Sorafinib® and tamoxifen. AR-12 has received IND acceptance by the FDA.




Publications

• OSU-03012, a Novel Celecoxib Derivative, Induces Reactive Oxygen Species–Related Autophagy in Hepatocellular Carcinoma
• Ping-Hui Tseng, Yu-Chieh Wang, Shu-Chuan Weng, et al., Overcoming Trastuzumab Resistance in HER2-Overexpressing Breast Cancer Cells by Using a Novel Celecoxib-Derived Phosphoinositide-Dependent Kinase-1 Inhibitor. Molecular Pharmacology 70:1534–1541, 2006.
• Wang et al., Targeting Endoplasmic Reticulum Stress and Akt with OSU-03012 and Gefitinib or Erlotinib to Overcome Resistance to Epidermal Growth Factor Receptor Inhibitors. Cancer Research 68, 2820-2830, April 2008. OSU-03012
• Weng SC, Kashida Y, Kulp SK et al., 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; 7(4):800-8.
• Li J, Zhu J, Melvin WS, Bekaii-Saab TS, Chen CS, Muscarella P. A structurally optimized celecoxib derivative inhibits human pancreatic cancer cell growth. J Gastrointest Surg. 2006 Feb;10(2):207-14.
• Cen L, Hsieh FC, Lin HJ, Chen CS, Qualman SJ and Lin J, PDK-1/AKT pathway as a novel therapeutic target in rhabdomyosarcoma cells using OSU-03012 compound. British Journal of Cancer (2007).
• Johnson AJ, Smith LL, Zhu J, Heerema NA et al., A novel celecoxib derivative, OSU03012, induces cytotoxicity in primary CLL cells and transformed B-cell lymphoma cell line via a caspase- and Bcl-2-independent mechanism. Blood 2005 105: 2504-2509.
• Prochia LP. Guerra M, Wang YC, Zhang Y et al., OSU-03012, A Celecoxib Derivative, Directly Targets p21 Activated Kinase. Molecular Pharmacology Fast Forward 2007; doi:10.1121/mol.107.037556.
• McCubrey JA, LaHair MM, and Franklin RA, OSU-03012 in the Treatment of Glioblastoma. Molecular Pharmacology 70:437-439, 2006.
• Sargeant AM, Klein RD, Rengel RC et al., Chemopreventive and Bioenergetic Signaling Effects of PDK1/Akt Pathway Inhibition in a Transgenic Mouse Model of Prostate Cancer. Toxicologic Pathology, 35:549-561, 2007.
• To K, Zhao Y, Hu JK, Wang M et al., The Phosphoinositide-Dependent Kinase-1 Inhibitor 2-Amino-N-[4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-acetamide (OSU-03012) Presents Y-Box Binding Portein-1 from Inducing Epidermal Growth Factor Receptor. Molecular Pharmacology 72:641-652, 2007.
• Tseng PH, Lin HP, Zhu J et al., Synergistic interactions between imatinib mesylate and the novel phosphoinositide-dependent kinase-1 inhibitor OSU-03012 in overcoming imatinib mesylate resistance. Blood, 15 May 2005 - Volume 105 - Number 10.
• Yacoub A, Park MA, Hanna D et al., OSU-03012 Promotes Caspase-Independent but PERK-, Cathepsin B-, BID-, and AIF-Dependent Killing of Transformed Cells. Molecular Pharmacology 70:589-603, 2006.
• Zhang S, Suvannasankha A, Crean C, White V et al., OSU-03012, a Novel Celecoxib Derivitave, Is Cytotoxic to Myeloma Cells and Acts through Multiple Mechanims. Clin Cancer Res 2007; 13(16).
• Zhu J, Huang JW, Tseng PH et al., From the Cyclooxygenase-2 Inhibitor Celecoxib to a Novel Class of 3-Phosphoinositide-Dependent Protein Kinase-1 Inhibitors. Cancer Research 64, 4309-4318, June 15, 2004.

• PERK-dependent regulation of HSP70 expression and the regulation of autophagy
  
  
• OSU-03012 Stimulates PKR-Like Endoplasmic Reticulum-Dependent Increases in 70-kDa Heat Shock Protein Expression, Attenuating Its Lethal Actions in Transformed Cells
  
  
• OSU-03012, a Novel Celecoxib Derivative, Induces Reactive Oxygen Species–Related Autophagy in Hepatocellular Carcinoma