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Arno Therapeutics, Inc.
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AR-12



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.




Publications

  • Abdulhameed MD, Hamza A, Zhan CG. Microscopic modes and free energies of 3-phosphoinositide-dependent kinase-1 (PDK1) binding with celecoxib and other inhibitors. J Phys Chem B. 2006 Dec 28;110(51):26365-74.
  • Alvarez FJ, Murahari S, Couto CG, Rosol TJ, Kulp SK, Chen CS, Kisseberth WC. 3-Phosphoinositide-dependent protein kinase-1/Akt signalling and inhibition in a canine prostate carcinoma cell line. Vet Comp Oncol. 2007 Mar;5(1):47-58.
  • Baryawno N, Sveinbjörnsson B, Eksborg S, Chen CS, Kogner P, Johnsen JI. Small-molecule inhibitors of phosphatidylinositol 3-kinase/Akt signaling inhibit Wnt/beta-catenin pathway cross-talk and suppress medulloblastoma growth. Cancer Res. 2010 Jan 1;70(1):266-76. Epub 2009 Dec 22.
  • 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).
  • Chiu HC, Kulp SK, Soni S, Wang D, Gunn JS, Schlesinger LS, Chen CS. Eradication of intracellular Salmonella enterica serovar Typhimurium with a small-molecule, host cell-directed agent. Antimicrob Agents Chemother. 2009 Dec;53(12):5236-44. Epub 2009 Oct 5.
  • 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.
  • 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.
  • 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.
  • Hsu CH, Chao YW, Feng WC, Yeh PY, Chen CS, Cheng AL. Sorafenib, a multi-target inhibitor, and OSU-03012, a phosphoinositide- dependent kinase-1 inhibitor, are synergistic in cytotoxicity against nasopharyngeal carcinoma cells. AACR Meeting Abstracts, Apr 2008; 2008: 1331.
  • 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.
  • 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.
  • 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.
  • McCubrey JA, LaHair MM, and Franklin RA, OSU-03012 in the Treatment of Glioblastoma. Molecular Pharmacology 70:437-439, 2006.
  • Park MA, Curiel DT, Koumenis C, Graf M, Chen CS, Fisher PB, Grant S, Dent P. PERK-dependent regulation of HSP70 expression and the regulation of autophagy. Autophagy. 2008 Apr 1;4(3):364-7. Epub 2008 Jan 17.
  • Park MA, Zhang G, Norris J, Hylemon PB, Fisher PB, Grant S, Dent P. Regulation of autophagy by ceramide-CD95-PERK signaling. Autophagy. 2008 Oct 1;4(7):929-31. Epub 2008 Oct 5.
  • 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.
  • 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.
  • 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.
  • Segerström L, Baryawno N, Sveinbjörnsson B, Johnsen JI, Kogner P. Effects of the PDK1-inhibitor OSU03012 and the PI3K inhibitor PI103 on neuroblastoma in vitro. 2009 AACR Poster Presentations.
  • Shah M, Kim H, Lopez-Bergmani P, Gaitonde S, De SK, Tcherpakov M, Dewing A, Yuan H, Riel-Mehan M, Krajewski S, Robertson G, Pellecchia M, Ronai Z. Targeting AKT and PDK1 in melanoma. Society for Melanoma Research: 2009 International Congress, Poster Abstracts.
  • 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.
  • To K, Zhao Y, Jiang H, Hu K, Wang M, Wu J, Lee C, Yokom DW, Stratford AL, Klinge U, Mertens PR, Chen CS, Bally M, Yapp D, Dunn SE. The phosphoinositide-dependent kinase-1 inhibitor 2-amino-N-[4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-acetamide (OSU-03012) prevents Y-box binding protein-1 from inducing epidermal growth factor receptor. Mol Pharmacol. 2007 Sep;72(3):641-52. Epub 2007 Jun 26.
  • 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.
  • 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.
  • 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.

Articles


  • 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

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