GPI-15427 - CAS 805242-85-7
Catalog number:
Not Intended for Therapeutic Use. For research use only.
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 induced significant sensitization to radiotherapy, representing a promising new treatment in the management of HNSCC.
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GPI-15427; GPI 15427; GPI15427.
Current Developer:
Guilford Pharmaceuticals, Inc. (acquired by MGI Pharma, Inc. in 2005)
1.Poly(ADP-ribose)polymerase inhibition counteracts cataract formation and early retinal changes in streptozotocin-diabetic rats.
Drel VR1, Xu W, Zhang J, Kador PF, Ali TK, Shin J, Julius U, Slusher B, El-Remessy AB, Obrosova IG. Invest Ophthalmol Vis Sci. 2009 Apr;50(4):1778-90. doi: 10.1167/iovs.08-2191. Epub 2008 Dec 20.
PURPOSE: This study evaluated the role for poly(ADP-ribose) polymerase (PARP) in diabetes-induced cataractogenesis and early retinal changes.
2.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.
Tentori L1, Muzi A, Dorio AS, Scarsella M, Leonetti C, Shah GM, Xu W, Camaioni E, Gold B, Pellicciari R, Dantzer F, Zhang J, Graziani G. Curr Cancer Drug Targets. 2010 Jun;10(4):368-83.
We recently demonstrated that poly(ADP-ribose) polymerase (PARP)-1 is involved in angiogenesis and tumour aggressiveness. In this study we have compared the influence of abrogation of PARP-1 expression by stable gene silencing to that of the pharmacological inhibition of cellular PARP activity using PARP-1/-2 inhibitors on the chemosensitivity of tumour cells to the wide spectrum methylating agent temozolomide (TMZ) and to the N3-adenine selective methylating agent {1-methyl-4-[1-methyl-4-(3-methoxysulfonylpropanamido)pyrrole-2-carboxamido]-pyrrole-2-carboxamido}propane (Me-Lex). Silencing of PARP-1 in melanoma or cervical carcinoma lines enhanced in vitro sensitivity to TMZ and Me- Lex, and induced a higher level of cell accumulation at the G2/M phase of cell cycle with respect to controls. GPI 15427, which inhibits both PARP-1 and PARP-2, increased sensitivity to TMZ and Me-Lex both in PARP-1-proficient and - deficient cells. However, it induced different cell cycle modulations depending on PARP-1 expression, provoking a G2/M arrest only in PARP-1 silenced cells.
3.Poly(ADP-ribose) polymerase (PARP) inhibition counteracts multiple manifestations of kidney disease in long-term streptozotocin-diabetic rat model.
Shevalye H1, Stavniichuk R, Xu W, Zhang J, Lupachyk S, Maksimchyk Y, Drel VR, Floyd EZ, Slusher B, Obrosova IG. Biochem Pharmacol. 2010 Apr 1;79(7):1007-14. doi: 10.1016/j.bcp.2009.11.018. Epub 2009 Nov 27.
Evidence for the important role for poly(ADP-ribose) polymerase (PARP) in the pathogenesis of diabetic nephropathy is emerging. We previously reported that PARP inhibitors counteract early Type 1 diabetic nephropathy. This study evaluated the role for PARP in kidney disease in long-term Type 1 diabetes. Control and streptozotocin-diabetic rats were maintained with or without treatment with the PARP inhibitor 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de] anthracen-3-one (GPI-15,427, Eisai Inc.), 30mgkg(-1)d(-1), for 26 weeks after first 2 weeks without treatment. PARP activity in the renal cortex was assessed by Western blot analysis of poly(ADP-ribosyl)ated proteins. Urinary albumin, isoprostane, and 8-hydroxy-2'-deoxyguanosine excretion, and renal concentrations of transforming growth factor-beta(1), vascular endothelial growth factor, soluble intercellular adhesion molecule-1, fibronectin, and nitrotyrosine were evaluated by ELISA, and urinary creatinine and renal lipid peroxidation products by colorimetric assays.
4.Poly(ADP-ribose) polymerase inhibition reverses nitrergic neurovascular dysfunctions in penile erectile tissue from streptozotocin-diabetic mice.
Nangle MR1, Cotter MA, Cameron NE. J Sex Med. 2010 Oct;7(10):3396-403. doi: 10.1111/j.1743-6109.2010.01835.x.
INTRODUCTION: Activation of the DNA repair enzyme, poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP), in response to hyperglycemia-driven oxidative/nitrosative stress, may be an important mechanism in the development of vascular and neural complications in diabetes mellitus. However, a role for PARP in diabetic erectile dysfunction (ED) has not been demonstrated.
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