title: GPI 6150 prevents H(2)O(2) cytotoxicity by inhibiting poly(ADP-ribose) polymerase.
abstract: GPI 6150 (1,11b-dihydro-[2H]benzopyrano[4,3,2-de]isoquinolin-3-one) is a novel inhibitor of poly(ADP-ribose) polymerase (PARP). It has demonstrated efficacy in rodent models of focal cerebral ischemia, traumatic brain injury, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine damage to dopaminergic neurons, regional myocardial ischemia, streptozotocin-induced diabetes, septic shock, and arthritis. Here we report the structure of GPI 6150, its enzymatic characteristics, and biochemical property in cytoprotection. As a competitive PARP inhibitor (K(i) = 60 nM), GPI 6150 protected the P388D1 cells against hydrogen peroxide cytotoxicity, by preventing PARP activation and the depletion of NAD(+), the substrate for PARP. To address the concerns of potential side effects of PARP inhibition, we tested GPI 6150 and found it had no effect on the repair and expression of a plasmid DNA damaged by N-methyl-N'-nitro-N-nitrosoguanidine. Neither did it affect dehydrogenases with NAD co-enzyme. GPI 6150 was much less potent to inhibit mono-ADP-ribosyltransferase. There was no selectivity for GPI 6150 between PARP isozymes. These attributes render GPI 6150 a useful tool to probe the functions of PARP.
authors.affiliation: Guilford Pharmaceuticals Inc., 6611 Tributary Street, Baltimore, Maryland, 21224, USA. zhang_j@guilfordpharm.com
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: S
authors.initials: S
authors.lastname: Lautar
authors.forename: S
authors.initials: S
authors.lastname: Huang
authors.forename: C
authors.initials: C
authors.lastname: Ramsey
authors.forename: A
authors.initials: A
authors.lastname: Cheung
authors.forename: J H
authors.initials: JH
authors.lastname: Li
mesh_terms: D036002:ADP Ribose Transferases; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects*; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000633:toxicity*; D007546:Isoquinolines / Q000494:pharmacology*; D007700:Kinetics; D007941:Leukemia P388 / Q000201:enzymology*; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D051379:Mice; D009243:NAD / Q000378:metabolism; D010957:Plasmids / Q000187:drug effects; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D001578:Benzopyrans; D004791:Enzyme Inhibitors; C417259:GPI 6150; D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009243:NAD; D008769:Methylnitronitrosoguanidine; D006861:Hydrogen Peroxide; D036002:ADP Ribose Transferases