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INO-1001

INO-1001 is an isoindolinone derivative and potent inhibitor of the nuclear enzyme poly (ADP-ribose) polymerase (PARP) with chemosensitization and radiosensitization properties. INO-1001 inhibits PARP, which may result in inhibition of tumor cell DNA repair mechanisms and, so, tumor cell resistance to chemotherapy and radiation therapy. PARP enzymes are activated by DNA breaks and have been implicated in the repair of DNA single-strand breaks (SSB). Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus) .

INO-1001, currently developed by Inotek Pharmaceuticals, is  known to sensitize cells to radiation in vitro by inhibiting the repair of DNA damage. Recent evidence has suggested that PARP inhibition may also be a way of selectively targeting p53 deficient cancer cells. The present study tested INO-1001 for its in vivo effect on the chemoresponse of two p53 deficient tumors, human breast cancer MDA-MB-231 and murine mammary carcinoma MCa-K.  Results showed that INO-1001 was highly effective in enhancing the anti-tumor effects of Doxorubicin for both MDA-MB-231 (EF=1.88) and MCa-K (EF=1.64). INO-1001 has high potential for enhancing the anti-tumor effects of chemotherapy agents such as Doxorubicin against p53 deficient breast cancer. For detail see: http://www.ncbi.nlm.nih.gov/pubmed/17628743.

Current developer:   Inotek Pharmaceuticals

1. Gartner, Elaina M.; Burger, Angelika M.; LoRusso, Patricia M. Poly(ADP-ribose) polymerase inhibitors a novel drug class with a promising future. Cancer Journal (Hagerstown, MD, United States) (2010), 16(2), 83-90. CODEN: CAJOCB ISSN:1528-9117. AN 2010:600123

2. Roesner, Jan P.; Mersmann, Jan; Bergt, Stefan; Bohnenberg, Karl; Barthuber, Carmen; Szabo, Csaba; Noeldge-Schomburg, Gabriele E. F.; Zacharowski, Kai. Therapeutic injection of PARP inhibitor INO-1001 preserves cardiac function in porcine myocardial ischemia and reperfusion without reducing infarct size. Shock (2010), 33(5), 507-512. CODEN: SAGUAI ISSN:1073-2322. AN 2010:486940

3. Maier, Christian Frank. Effects of the PARP-1 of inhibitor INO-1001 on ischemia reperfusion-associated organ damages after thoracic aortal cross-clamping on the pig. (2009), No pp. AN 2010:483793

4. Wang, Yaolin; Wang, Yan; Liu, Ming; Bishop, Walter Robert; Seidel-Dugan, Cynthia. Anti-IGF-1 receptor antibody combined with chemotherapeutic agent, antitumor agent, radiotherapy or surgery for treating or preventing colorectal cancer. PCT Int. Appl. (2009), 52pp. CODEN: PIXXD2 WO 2009142810 A2 20091126 CAN 151:569615 AN 2009:1470605

5. Wang, Yaolin; Wang, Yan; Lu, Brian Der-Hua; Liu, Ming; Seidel-Dugan, Cynthia; Yao, Siu-Long. Sequential administration of chemotherapeutic agents and anti-(insulin-like growth factor 1 receptor) for treatment of cancer. PCT Int. Appl. (2009), 104 pp. CODEN: PIXXD2 WO 2009137378 A2 20091112 CAN 151:521177 AN 2009:1395230

6. Boulares, Hamid A.; Hans, Chetan P.; Naura, Amarjit S. Regression of established atherosclerotic plaques, and treating sudden-onset asthma attacks, using PARP inhibitors. PCT Int. Appl. (2009), 27 pp. CODEN: PIXXD2 WO 2009126606 A2 20091015 CAN 151:440670 AN 2009:1262359

7. Mann, David Marshall. Gene expression profiling in the pulmonary artery in the selection of therapies for vascular-related diseases. PCT Int. Appl. (2009), 115pp. CODEN: PIXXD2 WO 2009121031 A1 20091001 CAN 151:418165 AN 2009:1194632

8. O'Malley, Bert W.; Abuzeid, Waleed M.; Li, Daqing. Anti-neoplastic combination therapeutic regimen involving co-disruption of PARP pathway and Mre11/Rad50/Nbs1 complex and compositons useful therein. PCT Int. Appl. (2009), 39 pp. CODEN: PIXXD2 WO 2009114459 A2 20090917 CAN 151:366712 AN 2009:1141539

9. Bedikian, Agop Y.; Papadopoulos, Nicholas E.; Kim, Kevin B.; Hwu, Wen-Jen; Homsi, Jade; Glass, Michelle R.; Cain, Suzanne; Rudewicz, Patrick; Vernillet, Laurent; Hwu, Patrick. A Phase IB Trial of Intravenous INO-1001 Plus Oral Temozolomide in Subjects with Unresectable Stage-III or IV Melanoma. Cancer Investigation (2009), 27(7), 756-763. CODEN: CINVD7 ISSN:0735-7907. CAN 152:303598 AN 2009:926179

10. Fink, Mitchell P. A method using a peroxynitrite decomposition agent or other agent for prevention of contrast-induced nephropathy. PCT Int. Appl. (2009), 99 pp. CODEN: PIXXD2 WO 2009088860 A2 20090716 CAN 151:164326 AN 2009:858783

11. Wang, Yan; Wang, Yaolin; Levitan, Diane; Seidel-Dugan, Cynthia; Liu, Ming; Ding, Wei. Gene expression biomarkers for detecting IGF1R inhibitor-resistant or -sensitive cancers and uses in anti-IGF1R antibody combination chemotherapy. PCT Int. Appl. (2009), 165pp. CODEN: PIXXD2 WO 2009079587 A2 20090625 CAN 151:116583 AN 2009:769153

12. Morrow, David A.; Brickman, Chaim M.; Murphy, Sabina A.; Baran, Kenneth; Krakover, Ricardo; Dauerman, Harold; Kumar, Sujatha; Slomowitz, Natanya; Grip, Laura; McCabe, Carolyn H.; Salzman, Andrew L. A randomized, placebo-controlled trial to evaluate the tolerability, safety, pharmacokinetics, and pharmacodynamics of a potent inhibitor of poly(ADP-ribose) polymerase (INO-1001) in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: results of the TIMI 37 trial. Journal of Thrombosis and Thrombolysis (2009), 27(4), 359-364. CODEN: JTTHFF ISSN:0929-5305. CAN 151:542837 AN 2009:574115

13. Ramachandra, Sumant; Bishop, Robert Walter; Masat, Linda; Huang, Chao Bai; Takeuchi, Toshihiko; Kantak, Seema. Human anti-VEGF antibodies and conjugates for treatment of angiogenesis conditions. PCT Int. Appl. (2009), 195pp. CODEN: PIXXD2 WO 2009055343 A2 20090430 CAN 150:492909 AN 2009:519479

14. Wang, Yan; Pachter, Jonathan A.; Hailey, Judith Anne; Brams, Peter; Williams, Denise; Srinivasan, Mohan; Feingersh, Mary Diane. Anti-insulin-like growth factor 1 receptor therapy. PCT Int. Appl. (2009), 129pp. CODEN: PIXXD2 WO 2009005673 A1 20090108 CAN 150:119716 AN 2009:25215

15. Dhein, S.; Krause, N.; Ullmann, C.; Flister, A.; Lehmann, S.; Muth, P.; Walther, T.; Kostelka, M.; Mohr, F. W. Ischemic and inflammatory lung impairment by extracorporeal circulation: Effect of PARP-inhibition by INO1001. Pharmacological Research (2008), 58(5-6), 332-339. CODEN: PHMREP ISSN:1043-6618. CAN 150:530685 AN 2008:1442900

16. Maier, Christian; Scheuerle, Angelika; Hauser, Balazs; Schelzig, Hubert; Szabo, Csaba; Radermacher, Peter; Kick, Jochen. The selective poly(ADP)ribose-polymerase 1 inhibitor INO1001 reduces spinal cord injury during porcine aortic cross-clamping-induced ischemia/reperfusion injury. Intensive Care Medicine (2007), 33(5), 845-850. CODEN: ICMED9 ISSN:0342-4642. CAN 150:159887 AN 2008:1096402

17. Wang, Yan; Zong, Chen; Seidel-Dugan, Cynthia; Wang, Yaolin; Yao, Siu-Long; Lu, Brian Der-Hua; Ladha, Mohamed H. Methods of treating cancer using IGF1R inhibitors. PCT Int. Appl. (2008), 103pp. CODEN: PIXXD2 WO 2008076278 A2 20080626 CAN 149:102715 AN 2008:771165

18. Biro, Alexander; Katzir, Ze'ev. Combination of an aminoglycoside antibiotic and a poly(ADP-ribose) polymerase (PARP) inhibitor for the treatment of aminoglycoside antibiotic-associated nephrotoxicity. PCT Int. Appl. (2008), 43pp. CODEN: PIXXD2 WO 2008050339 A2 20080502 CAN 148:509922 AN 2008:529810

19. McCourtie, Anton S.; Farivar, Alexander S.; Woolley, Steven M.; Merry, Heather E.; Wolf, Patrick S.; Szabo, Csaba; Mulligan, Michael S. Poly (ADP) ribose synthetase inhibition in alveolar macrophages undergoing hypoxia and reoxygenation. Experimental and Molecular Pathology (2008), 84(2), 141-144. CODEN: EXMPA6 ISSN:0014-4800. CAN 149:6514 AN 2008:406563

20. Ashworth, Alan; Lord, Christopher James; Turner, Nicholas Charles. Methods of increasing the sensitivity of cancer cells to DNA damage. PCT Int. Appl. (2008), 96 pp. CODEN: PIXXD2 WO 2008020180 A2 20080221 CAN 148:276718 AN 2008:223698

21. Mason, Kathryn A.; Valdecanas, David; Hunter, Nancy R.; Milas, Luka. INO-1001, a novel inhibitor of poly(ADP-ribose) polymerase, enhances tumor response to doxorubicin. Investigational New Drugs (2008), 26(1), 1-5. CODEN: INNDDK ISSN:0167-6997. CAN 148:486493 AN 2008:52293

22. Wang, Yan. Blood levels of insulin-like growth factor-binding protein 2 as a marker for monitoring the effectiveness of inhibitors of insulin-like growth factor I receptors in cancer therapy. PCT Int. Appl. (2008), 133pp. CODEN: PIXXD2 WO 2008005469 A2 20080110 CAN 148:135980 AN 2008:43490

23. Radovits, Tamas; Zotkina, Julia; Lin, Li-ni; Boemicke, Timo; Arif, Rawa; Gero, Domokos; Horvath, Eszter M.; Karck, Matthias; Szabo, Csaba; Szabo, Gabor. Poly(ADP-ribose) polymerase inhibition improves endothelial dysfunction induced by hypochlorite. Experimental Biology and Medicine (Maywood, NJ, United States) (2007), 232(9), 1204-1212. CODEN: EBMMBE ISSN:1535-3702. CAN 147:439969 AN 2007:1164877

24. Scotto, Kathleen A.; Mandola, Michael. Use of PARP-1 inhibitors for improvement of the cytotoxic effect of ecteinascidin-743 in the treatment of cancer. PCT Int. Appl. (2007), 16 pp. CODEN: PIXXD2 WO 2007062413 A2 20070531 CAN 147:2005 AN 2007:591050

25. Radovits, Tamas; Seres, Leila; Gero, Domokos; Berger, Irina; Szabo, Csaba; Karck, Matthias; Szabo, Gabor. Single dose treatment with PARP-inhibitor INO-1001 improves aging-associated cardiac and vascular dysfunction. Experimental Gerontology (2007), 42(7), 676-685. CODEN: EXGEAB ISSN:0531-5565. CAN 147:314621 AN 2007:559263

26. Radovits, Tamas; Lin, Li-ni; Zotkina, Julia; Gero, Domokos; Szabo, Csaba; Karck, Matthias; Szabo, Gabor. Poly(ADP-ribose) polymerase inhibition improves endothelial dysfunction induced by reactive oxidant hydrogen peroxide in vitro. European Journal of Pharmacology (2007), 564(1-3), 158-166. CODEN: EJPHAZ ISSN:0014-2999. CAN 147:133628 AN 2007:524150

27. Yasuhiro, Tetsuya; Kitajima, Takashi; Wakamatsu, Daisuke; Kamoshima, Wataru. Agent for reduction of bleeding in cerebrovascular disorder. PCT Int. Appl. (2006), 44pp. CODEN: PIXXD2 WO 2006137510 A1 20061228 CAN 146:93553 AN 2006:1357083

28. Szabo, Csaba; Biser, Alisha; Benko, Rita; Bottinger, Erwin; Susztak, Katalin. Poly(ADP-ribose) polymerase inhibitors ameliorate nephropathy of type 2 diabetic Leprdb/db mice. Diabetes (2006), 55(11), 3004-3012. CODEN: DIAEAZ ISSN:0012-1797. CAN 146:114727 AN 2006:1198396

29. Beller, Carsten J.; Kosse, Jens; Radovits, Tamas; Geroe, Domokos; Krempien, Robert; Gross, Marie-Luise; Berger, Irina; Hagl, Siegfried; Szabo, Csaba; Szabo, Gabor. Poly(ADP-ribose) polymerase inhibition combined with irradiation: a dual treatment concept to prevent neointimal hyperplasia after endarterectomy. International Journal of Radiation Oncology, Biology, Physics (2006), 66(3), 867-875. CODEN: IOBPD3 ISSN:0360-3016. CAN 146:513885 AN 2006:1023433

30. Beller, Carsten J.; Radovits, Tamas; Seres, Leila; Kosse, Jens; Krempien, Robert; Gross, Marie-Luise; Penzel, Roland; Berger, Irina; Huber, Peter E.; Hagl, Siegfried; Szabo, Csaba; Szabo, Gabor. Poly(ADP-ribose) polymerase inhibition reverses vascular dysfunction after  -irradiation. International Journal of Radiation Oncology, Biology, Physics (2006), 65(5), 1528-1535. CODEN: IOBPD3 ISSN:0360-3016. CAN 146:220587 AN 2006:739116

31. Szabo, Gabor; Baehrle, Susanne; Stumpf, Nicole; Szabo, Csaba; Hagl, Siegfried. Contractile dysfunction in experimental cardiac allograft rejection: role of the poly (ADP-ribose) polymerase pathway. Transplant International (2006), 19(6), 506-513. CODEN: TRINE5 ISSN:0934-0874. CAN 145:483451 AN 2006:659829

32. Hauser, Balazs; Groeger, Michael; Ehrmann, Ulrich; Albicini, Maura; Brueckner, Uwe Bernd; Schelzig, Hubert; Venkatesh, Balasubramanian; Li, Hongshan; Szabo, Csaba; Speit, Guenter; Radermacher, Peter; Kick, Jochen. The PARP-1 inhibitor INO-1001 facilitates hemodynamic stabilization without affecting DNA repair in porcine thoracic aortic cross-clamping-induced ischemia/reperfusion. Shock (2006), 25(6), 633-640. CODEN: SAGUAI ISSN:1073-2322. CAN 145:431947 AN 2006:583501

33. Toth, Orsolya; Szabo, Csaba; Kecskes, Marianna; Poto, Laszlo; Nagy, Agnes; Losonczy, Hajna. In vitro effect of the potent poly(ADP-ribose) polymerase (PARP) inhibitor INO-1001 alone and in combination with aspirin, eptifibatide, tirofiban, enoxaparin, or alteplase on haemostatic parameters. Life Sciences (2006), 79(4), 317-323. CODEN: LIFSAK ISSN:0024-3205. CAN 145:201990 AN 2006:536823

34. Hellstrand, Kristoffer; Hermodsson, Svante; Thoren, Fredrik; Romero, Ana. Use of parp-1 inhibitors for protecting tumorcidal lymphocytes from apoptosis. PCT Int. Appl. (2006), 42 pp. CODEN: PIXXD2 WO 2006039545 A2 20060413 CAN 144:363088 AN 2006:343963

35. Wang, Xi; Satoh, Hiroko; Kase, Hiroyuki; Suzuki, Kunihiro; Iwata, Chigusa; Hattori, Yoshiyuki; Kasai, Kikuo. Effect of poly(ADP-ribose) polymerase inhibitors on hypoadiponectinemia caused by chronic blockade of nitric oxide synthesis in rats. Dokkyo Journal of Medical Sciences (2005), 32(2), 85-89. CODEN: DJMSDB ISSN:0385-5023. CAN 145:202427 AN 2006:281206

36. Ye, Diana Z.; Tai, Mei-Hui; Linning, Katrina D.; Szabo, Csaba; Olson, L. Karl. MafA expression and insulin promoter activity are induced by nicotinamide and related compounds in INS-1 pancreatic  -cells. Diabetes (2006), 55(3), 742-750. CODEN: DIAEAZ ISSN:0012-1797. CAN 144:381740 AN 2006:241121

37. Pacher, Pal; Liaudet, Lucas; Mabley, Jon G.; Cziraki, Attila; Hasko, Gyorgy; Szabo, Csaba. Beneficial effects of a novel ultrapotent poly(ADP-ribose) polymerase inhibitor in murine models of heart failure. International Journal of Molecular Medicine (2006), 17(2), 369-375. CODEN: IJMMFG ISSN:1107-3756. CAN 145:95893 AN 2006:143526

38. Kendirci, Muammer; Zsengeller, Zsuzsanna; Bivalacqua, Trinity J.; Gur, Serap; Usta, Mustafa F.; Chen, Min; Szabo, Csaba; Hellstrom, Wayne J. G. Poly(Adenosine Diphosphate-Ribose) Polymerase Inhibition Preserves Erectile Function in Rats After Cavernous Nerve Injury. Journal of Urology (Hagerstown, MD, United States) (2005), 174(5), 2054-2059. CODEN: JOURAA ISSN:0022-5347. CAN 144:184446 AN 2005:1098566

39. Cheng, C. Lynn; Johnson, Stewart P.; Keir, Stephen T.; Quinn, Jennifer A.; Ali-Osman, Francis; Szabo, Csaba; Li, Hongshan; Salzman, Andrew L.; Dolan, M. Eileen; Modrich, Paul; Bigner, Darell D.; Friedman, Henry S. Poly(ADP-ribose) polymerase-1 inhibition reverses temozolomide resistance in a DNA mismatch repair-deficient malignant glioma xenograft. Molecular Cancer Therapeutics (2005), 4(9), 1364-1368. CODEN: MCTOCF ISSN:1535-7163. CAN 143:318623 AN 2005:1064573

40. Brownlee, Michael A. Glp-1 (9-36) methods and compositions. PCT Int. Appl. (2005), 28 pp. CODEN: PIXXD2 WO 2005060986 A1 20050707 CAN 143:91055 AN 2005:588685

41. Brownlee, Michael. Use of poly(ADP-ribose) polymerase inhibitors for prevention and treatment of diabetic and insulin resistance complications. PCT Int. Appl. (2005), 52 pp. CODEN: PIXXD2 WO 2005037990 A2 20050428 CAN 142:428133 AN 2005:371374

42. Besson, Valerie C.; Zsengeller, Zsuzsanna; Plotkine, Michel; Szabo, Csaba; Marchand-Verrecchia, Catherine. Beneficial effects of PJ34 and INO-1001, two novel water-soluble poly(ADP-ribose) polymerase inhibitors, on the consequences of traumatic brain injury in rat. Brain Research (2005), 1041(2), 149-156. CODEN: BRREAP ISSN:0006-8993. CAN 142:441744 AN 2005:319312

43. Xiao, Chun-Yang; Chen, Min; Zsengeller, Zsuzsanna; Li, Hongshan; Kiss, Levente; Kollai, Mark; Szabo, Csaba. Poly(ADP-ribose) polymerase promotes cardiac remodeling, contractile failure, and translocation of apoptosis-inducing factor in a murine experimental model of aortic banding and heart failure. Journal of Pharmacology and Experimental Therapeutics (2005), 312(3), 891-898. CODEN: JPETAB ISSN:0022-3565. CAN 142:237688 AN 2005:207276

44. Szabo, Gabor; Soos, Pal; Mandera, Susanne; Heger, Ulrike; Flechtenmacher, Christa; Seres, Leila; Zsengeller, Zsuzsanna; Sack, Falk-Udo; Szabo, Csaba; Hagl, Siegfried. Mesenteric injury after cardiopulmonary bypass: Role of poly(adenosine 5'-diphosphate-ribose) polymerase. Critical Care Medicine (2004), 32(12), 2392-2397. CODEN: CCMDC7 ISSN:0090-3493. CAN 142:290973 AN 2004:1079106

45. Szabo, Csaba; Pacher, Pal; Zsengeller, Zsuzsanna; Vaslin, Anne; Komjati, Katalin; Benko, Rita; Chen, Min; Mabley, Jon G.; Kollai, Mark. Angiotensin II-mediated endothelial dysfunction: role of poly(ADP-ribose) polymerase activation. Molecular Medicine (Manhasset, NY, United States) (2004), 10(1-6), 28-35. CODEN: MOMEF3 ISSN:1076-1551. CAN 142:53712 AN 2004:1039127

46. Pacher, Pal; Vaslin, Anne; Benko, Rita; Mabley, Jon G.; Liaudet, Lucas; Hasko, Gyoergy; Marton, Anita; Batkai, Sandor; Kollai, Mark; Szabo, Csaba. A new, potent poly(ADP-ribose) polymerase inhibitor improves cardiac and vascular dysfunction associated with advanced aging. Journal of Pharmacology and Experimental Therapeutics (2004), 311(2), 485-491. CODEN: JPETAB ISSN:0022-3565. CAN 141:360429 AN 2004:906862

47. Xiao, Chun-Yang; Chen, Min; Zsengeller, Zsuzsanna; Szabo, Csaba. Poly(ADP-ribose) polymerase contributes to the development of myocardial infarction in diabetic rats and regulates the nuclear translocation of apoptosis-inducing factor. Journal of Pharmacology and Experimental Therapeutics (2004), 310(2), 498-504. CODEN: JPETAB ISSN:0022-3565. CAN 141:138311 AN 2004:608715

48. Benko, Rita; Pacher, Pal; Vaslin, Anne; Kollai, Mark; Szabo, Csaba. Restoration of the endothelial function in the aortic rings of apolipoprotein E deficient mice by pharmacological inhibition of the nuclear enzyme poly(ADP-ribose) polymerase. Life Sciences (2004), 75(10), 1255-1261. CODEN: LIFSAK ISSN:0024-3205. CAN 141:171979 AN 2004:519866

49. Szabo, Gabor; Soos, Pal; Mandera, Susanne; Heger, Ulrike; Flechtenmacher, Christa; Baehrle, Susanne; Seres, Leila; Cziraki, Attila; Gries, Andre; Zsengeller, Zsuszanna; Vahl, Christian F.; Hagl, Siegfried; Szabo, Csaba. INO-1001 a novel poly(ADP-ribose) polymerase (PARP) inhibitor improves cardiac and pulmonary function after crystalloid cardioplegia and extracorporal circulation. Shock (2004), 21(5), 426-432. CODEN: SAGUAI ISSN:1073-2322. CAN 141:388392 AN 2004:420231

50. Murakami, Kazunori; Enkhbaatar, Perenlei; Shimoda, Katsumi; Cox, Robert A.; Burke, Ann S.; Hawkins, Hal K.; Traber, Lillian D.; Schmalstieg, Frank C.; Salzman, Andrew L.; Mabley, Jon G.; Komjati, Katalin; Pacher, Pal; Zzengeller, Zsuzsanna; Szabo, Csaba; Traber, Daniel L. Inhibition of poly(ADP-ribose) polymerase attenuates acute lung injury in an ovine model of sepsis. Shock (2004), 21(2), 126-133. CODEN: SAGUAI ISSN:1073-2322. CAN 140:421712 AN 2004:301889