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OSU-03012

OSU-03012 is a novel celecoxib derivative, without cyclooxygenase-2 inhibitory activity, capable of inducing apoptosis in various cancer cells types, and is being developed as an anticancer drug. OSU-03012 is cytotoxic to MM cells with mean LC₅₀ 3.69 ± 0.23 and 6.25 ± 0.86 μmol/L and at 24 h for primary MM cells and cell lines, respectively. As a known PDK-1 inhibitor, OSU-03012 inhibited the PI3K/Akt pathway with downstream effects on BAD, GSK-3β, FoxO1a, p70S6K, and MDM-2. see http://clincancerres.aacrjournals.org/content/13/16/4750.abstract.

Current developer: 

 1: 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.

2: 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.

3: 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.

4: 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.

5: 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.

6: 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.

7: 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.

8: 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.

9: 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.

10: Wang YC, Kulp SK, Wang D, Yang CC, Sargeant AM, Hung JH, Kashida Y, Yamaguchi M, Chang GD, Chen CS. Targeting endoplasmic reticulum stress and Akt with OSU-03012 and gefitinib or erlotinib to overcome resistance to epidermal growth factor receptor inhibitors. Cancer Res. 2008 Apr 15;68(8):2820-30. PubMed PMID: 18413750.

11: Schönthal AH, Chen TC, Hofman FM, Louie SG, Petasis NA. Celecoxib analogs that lack COX-2 inhibitory function: preclinical development of novel anticancer drugs. Expert Opin Investig Drugs. 2008 Feb;17(2):197-208. Review. PubMed PMID: 18230053.

12: 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. PubMed PMID: 18216498.

13: Park MA, Yacoub A, Rahmani M, Zhang G, Hart L, Hagan MP, Calderwood SK, Sherman MY, Koumenis C, Spiegel S, Chen CS, Graf M, Curiel DT, Fisher PB, Grant S, Dent P. OSU-03012 stimulates PKR-like endoplasmic reticulum-dependent increases in 70-kDa heat shock protein expression, attenuating its lethal actions in transformed cells. Mol Pharmacol. 2008 Apr;73(4):1168-84. Epub 2008 Jan 8. PubMed PMID: 18182481; PubMed Central PMCID: PMC2674576.

14: Cen L, Hsieh FC, Lin HJ, Chen CS, Qualman SJ, Lin J. PDK-1/AKT pathway as a novel therapeutic target in rhabdomyosarcoma cells using OSU-03012 compound. Br J Cancer. 2007 Sep 17;97(6):785-91. PubMed PMID: 17848913; PubMed Central PMCID: PMC2360380.

15: Zhang S, Suvannasankha A, Crean CD, White VL, Johnson A, Chen CS, Farag SS. OSU-03012, a novel celecoxib derivative, is cytotoxic to myeloma cells and acts through multiple mechanisms. Clin Cancer Res. 2007 Aug 15;13(16):4750-8. PubMed PMID: 17699852.

16: Porchia LM, Guerra M, Wang YC, Zhang Y, Espinosa AV, Shinohara M, Kulp SK, Kirschner LS, Saji M, Chen CS, Ringel MD. 2-amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenyl} acetamide (OSU-03012), a celecoxib derivative, directly targets p21-activated kinase. Mol Pharmacol. 2007 Nov;72(5):1124-31. Epub 2007 Aug 2. PubMed PMID: 17673571.

17: Ryan EP, Bushnell TP, Friedman AE, Rahman I, Phipps RP. Cyclooxygenase-2 independent effects of cyclooxygenase-2 inhibitors on oxidative stress and intracellular glutathione content in normal and malignant human B-cells. Cancer Immunol Immunother. 2008 Mar;57(3):347-58. Epub 2007 Aug 1. PubMed PMID: 17668203.

18: 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]-ace tamide (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. PubMed PMID: 17595327.

19: 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. PubMed PMID: 19754801.

20: Tseng PH, Wang YC, Weng SC, Weng JR, Chen CS, Brueggemeier RW, Shapiro CL, Chen CY, Dunn SE, Pollak M, Chen CS. Overcoming trastuzumab resistance in HER2-overexpressing breast cancer cells by using a novel celecoxib-derived phosphoinositide-dependent kinase-1 inhibitor. Mol Pharmacol. 2006 Nov;70(5):1534-41. Epub 2006 Aug 3. PubMed PMID: 16887935.

21: McCubrey JA, Lahair MM, Franklin RA. OSU-03012 in the treatment of glioblastoma. Mol Pharmacol. 2006 Aug;70(2):437-9. Epub 2006 May 4. PubMed PMID: 16675657.

22: Yacoub A, Park MA, Hanna D, Hong Y, Mitchell C, Pandya AP, Harada H, Powis G, Chen CS, Koumenis C, Grant S, Dent P. OSU-03012 promotes caspase-independent but PERK-, cathepsin B-, BID-, and AIF-dependent killing of transformed cells. Mol Pharmacol. 2006 Aug;70(2):589-603. Epub 2006 Apr 18. PubMed PMID: 16622074.

23: 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. PubMed PMID: 16455452.

24: Devarenne TP, Ekengren SK, Pedley KF, Martin GB. Adi3 is a Pdk1-interacting AGC kinase that negatively regulates plant cell death. EMBO J. 2006 Jan 11;25(1):255-65. Epub 2005 Dec 15. PubMed PMID: 16362044; PubMed Central PMCID: PMC1356353.

25: Kucab JE, Lee C, Chen CS, Zhu J, Gilks CB, Cheang M, Huntsman D, Yorida E, Emerman J, Pollak M, Dunn SE. Celecoxib analogues disrupt Akt signaling, which is commonly activated in primary breast tumours. Breast Cancer Res. 2005;7(5):R796-807. Epub 2005 Aug 1. PubMed PMID: 16168126; PubMed Central PMCID: PMC1242152.

26: Tong Z, Wu X, Ovcharenko D, Zhu J, Chen CS, Kehrer JP. Neutrophil gelatinase-associated lipocalin as a survival factor. Biochem J. 2005 Oct 15;391(Pt 2):441-8. PubMed PMID: 16060857; PubMed Central PMCID: PMC1276944.

27: Carón RW, Yacoub A, Li M, Zhu X, Mitchell C, Hong Y, Hawkins W, Sasazuki T, Shirasawa S, Kozikowski AP, Dennis PA, Hagan MP, Grant S, Dent P. Activated forms of H-RAS and K-RAS differentially regulate membrane association of PI3K, PDK-1, and AKT and the effect of therapeutic kinase inhibitors on cell survival. Mol Cancer Ther. 2005 Feb;4(2):257-70. PubMed PMID: 15713897.

28: Tseng PH, Lin HP, Zhu J, Chen KF, Hade EM, Young DC, Byrd JC, Grever M, Johnson K, Druker BJ, Chen CS. Synergistic interactions between imatinib mesylate and the novel phosphoinositide-dependent kinase-1 inhibitor OSU-03012 in overcoming imatinib mesylate resistance. Blood. 2005 May 15;105(10):4021-7. Epub 2005 Jan 21. PubMed PMID: 15665113; PubMed Central PMCID: PMC1895085.

29: Johnson AJ, Smith LL, Zhu J, Heerema NA, Jefferson S, Mone A, Grever M, Chen CS, Byrd JC. 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 Mar 15;105(6):2504-9. Epub 2004 Sep 28. PubMed PMID: 15454489.

30: Zhu J, Huang JW, Tseng PH, Yang YT, Fowble J, Shiau CW, Shaw YJ, Kulp SK, Chen CS. From the cyclooxygenase-2 inhibitor celecoxib to a novel class of 3-phosphoinositide-dependent protein kinase-1 inhibitors. Cancer Res. 2004 Jun 15;64(12):4309-18. PubMed PMID: 15205346.