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  GPI-15427

GPI 15427 is a potent PARP-1 inhibitor capable of crossing the blood-brain barrier, which can significantly increased the antitumor activity of the methylating agent TMZ against malignant melanoma, glioblastoma multiforme, or lymphoma growing at the CNS site. GPI-15427 acts as a potent inhibitor of the enzyme, being capable of inhibiting the activity of purified PARP-1 at nanomolar concentrations.

GPI 15427 + radiation significantly reduced tumor volume compared to vehicle treated mice and mice treated with GPI 15427 alone or mice treated with radiation alone. In conclusion, these data indicate that iv administration of the PARP inhibitor GPI 15427 is well tolerated and induces significant enhancement of radiation anti-tumor efficacy against human head and neck cancer. (source: http://aacrmeetingabstracts.org/cgi/content/abstract/2004/1/311-c).

Current developer:    Guilford Pharmaceuticals, Inc. (acquired by MGI Pharma, Inc. in 2005)

1. N-methylpurine DNA glycosylase and polymerase beta as biomarkers for alkylator chemotherapy potentiation By Sobol, Robert W., Jr.; Tang, Jiangbo From U.S. Pat. Appl. Publ. (2011), US 20110245309 A1 20111006.

2. Poly(ADP-ribose) polymerase inhibition reverses nitrergic neurovascular dysfunctions in penile erectile tissue from streptozotocin-diabetic mice By Nangle, Matthew R.; Cotter, Mary A.; Cameron, Norman E. From Journal of Sexual Medicine (2010), 7(10), 3396-3403.

3. PARP1 is activated at telomeres upon G4 stabilization: possible target for telomere-based therapy By Salvati, E.; Scarsella, M.; Porru, M.; Rizzo, A.; Iachettini, S.; Tentori, L.; Graziani, G.; D'Incalci, M.; Stevens, M. F. G.; Orlandi, A.; et al From Oncogene (2010), 29(47), 6280-6293.

4. Pharmacological inhibition of poly(ADP-ribose) polymerase (PARP) activity in PARP-1 silenced tumour cells increases chemosensitivity to temozolomide and to a N3-adenine selective methylating agent By Tentori, L.; Muzi, A.; Dorio, A. S.; Scarsella, M.; Leonetti, C.; Shah, G. M.; Xu, W.; Camaioni, E.; Gold, B.; Pellicciari, R.; et al From Current Cancer Drug Targets (2010), 10(4), 368-383.

5. New therapeutic and biomarker discovery for peripheral diabetic neuropathy: PARP inhibitor, nitrotyrosine, and tumor necrosis factor-α By Drel, Viktor R.; Lupachyk, Sergey; Shevalye, Hanna; Vareniuk, Igor; Xu, Weizheng; Zhang, Jie; Delamere, Nicholas A.; Shahidullah, Mohammad; Slusher, Barbara; Obrosova, Irina G. From Endocrinology (2010), 151(6), 2547-2555.

6. Poly(ADP-ribose) polymerase (PARP) inhibition counteracts multiple manifestations of kidney disease in long-term streptozotocin-diabetic rat model By Shevalye, Hanna; Stavniichuk, Roman; Xu, Weizheng; Zhang, Jie; Lupachyk, Sergey; Maksimchyk, Yury; Drel, Viktor R.; Floyd, Elizabeth Z.; Slusher, Barbara; Obrosova, Irina G. From Biochemical Pharmacology (2010), 79(7), 1007-1014.

7. Regression of established atherosclerotic plaques, and treating sudden-onset asthma attacks, using PARP inhibitors By Boulares, Hamid A.; Hans, Chetan P.; Naura, Amarjit S. From PCT Int. Appl. (2009), WO 2009126606 A2 20091015.

8. Pharmacological inhibition of poly(ADP-ribose) polymerase activity down-regulates the expression of syndecan-4 and Id-1 in endothelial cells By Lacal, Pedro Miguel; Tentori, Lucio; Muzi, Alessia; Ruffini, Federica; Dorio, Annalisa Susanna; Xu, Weizheng; Arcelli, Diego; Zhang, Jie; Graziani, Grazia From International Journal of Oncology (2009), 34(3), 861-872.

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9. PARP inhibition or gene deficiency counteracts intraepidermal nerve fiber loss and neuropathic pain in advanced diabetic neuropathy By Obrosova, Irina G.; Xu, Weizheng; Lyzogubov, Valeriy V.; Ilnytska, Olga; Mashtalir, Nazar; Vareniuk, Igor; Pavlov, Ivan A.; Zhang, Jie; Slusher, Barbara; Drel, Viktor R. From Free Radical Biology & Medicine (2008), 44(6), 972-981.

10. Preparation of substituted pyrimidoquinolines and thienoquinolines as serine-threonine protein kinase and PARP modulators By Chua, Peter C.; Pierre, Fabrice; Whitten, Jeffrey P. From PCT Int. Appl. (2008), WO 2008028168 A2 20080306.

11. Use of interleukin 6 (IL-6) in the diagnosis and treatment of neuroinflammatory conditions By Kerr, Douglas A.; Kaplin, Adam I.; Krishnan, Chitra From PCT Int. Appl. (2008), WO 2008016707 A2 20080207.

12. Poly(ADP-ribose) polymerase (PARP) inhibition or PARP-1 gene deletion reduces angiogenesis By Tentori, Lucio; Lacal, Pedro Miguel; Muzi, Alessia; Dorio, Annalisa Susanna; Leonetti, Carlo; Scarsella, Marco; Ruffini, Federica; Xu, Weizheng; Min, Wokee; Stoppacciaro, Antonella; et al From European Journal of Cancer (2007), 43(14), 2124-2133.

13. Methods and compositions to improve activity and reduce toxicity of stents By Au, Jessie L.S.; Wientjes, Guillaume M. From PCT Int. Appl. (2007), WO 2007065016 A2 20070607.

14. Agent for reduction of bleeding in cerebrovascular disorder By Yasuhiro, Tetsuya; Kitajima, Takashi; Wakamatsu, Daisuke; Kamoshima, Wataru From PCT Int. Appl. (2006), WO 2006137510 A1 20061228.

15. Antitumor sustained-release injection containing taxane and its synergistic agent By Liu, Yuyan From Faming Zhuanli Shenqing Gongkai Shuomingshu (2006), CN 1846687 A 20061018.

16. Inhibition of poly(ADP-ribose) polymerase prevents irinotecan-induced intestinal damage and enhances irinotecan/temozolomide efficacy against colon carcinoma By Tentori, Lucio; Leonetti, Carlo; Scarsella, Marco; Muzi, Alessia; Mazzon, Emanuela; Vergati, Matteo; Forini, Olindo; Lapidus, Rena; Xu, Weizheng; Dorio, Annalisa Susanna; et al From FASEB Journal (2006), 20(10), 1709-1711, 10.1096/fj.06-5916fje.

17. An anticancer implant composition containing vasoinhibitor/DNA inhibitor By Kong, Qingzhong; Sun, Juan; Tian, Shaolan From Faming Zhuanli Shenqing Gongkai Shuomingshu (2006), CN 1733305 A 20060215.

18. Treatment with PARP-1 inhibitors, GPI 15427 or GPI 16539, ameliorates intestinal damage in rat models of colitis and shock By Di Paola, Rosanna; Mazzon, Emanuela; Xu, Weizheng; Genovese, Tiziana; Ferrraris, Dana; Muia, Carmelo; Crisafulli, Concetta; Zhang, Jie; Cuzzocrea, Salvatore From European Journal of Pharmacology (2005), 527(1-3), 163-171.

19. Brain distribution and efficacy as chemosensitizer of an oral formulation of PARP-1 inhibitor GPI 15427 in experimental models of CNS tumors By Tentori, Lucio; Leonetti, Carlo; Scarsella, Marco; Vergati, Matteo; Xu, Weizheng; Calvin, David; Morgan, Lisa; Tang, Zhaocheng; Woznizk, Krystyna; Alemu, Christina; et al From International Journal of Oncology (2005), 26(2), 415-422.

20. Preparation of fused tricyclic nitrogen compounds as poly(ADP-ribose) polymerase inhibitors By Kalish, Vincent J.; Zhang, Jie; Xu, Weizheng; Li, Jia-He; Xing, Amy D. From PCT Int. Appl. (2004), WO 2004105700 A2 20041209.

21. Systemic Administration of GPI 15427, a Novel Poly(ADP-Ribose) Polymerase-1 Inhibitor, Increases the Antitumor Activity of Temozolomide against Intracranial Melanoma, Glioma, Lymphoma By Tentori, Lucio; Leonetti, Carlo; Scarsella, Marco; D'Amati, Giulia; Vergati, Matteo; Portarena, Ilaria; Xu, Weizheng; Kalish, Vincent; Zupi, Gabriella; Zhang, Jie; et al From Clinical Cancer Research (2003), 9(14), 5370-5379.