AR-12 is a PI3-k/Akt pathway inhibitor that also possesses activity in the endoplasmic reticulum (ER) stress and other pathways targeting apoptosis. 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. Arno plans to initiate Phase I studies of AR-12 in early 2009.




Publications

• 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.