title: Failure of iniparib to inhibit poly(ADP-Ribose) polymerase in vitro.
abstract: OBJECTIVE
  Poly(ADP-ribose) polymerase (PARP) inhibitors are undergoing extensive clinical testing for their single-agent activity in homologous recombination (HR)-deficient tumors and ability to enhance the action of certain DNA-damaging agents. Compared with other PARP inhibitors in development, iniparib (4-iodo-3-nitrobenzamide) is notable for its simple structure and the reported ability of its intracellular metabolite 4-iodo-3-nitrosobenzamide to covalently inhibit PARP1 under cell-free conditions. The present preclinical studies were conducted to compare the actions iniparib with the more extensively characterized PARP inhibitors olaparib and veliparib.
  
  
  METHODS
  The abilities of iniparib, olaparib, and veliparib to (i) selectively induce apoptosis or inhibit colony formation in HR-deficient cell lines, (ii) selectively sensitize HR-proficient cells to topoisomerase I poisons, and (iii) inhibit formation of poly(ADP-ribose) polymer (pADPr) in intact cells were compared.
  
  
  RESULTS
  Consistent with earlier reports, olaparib and veliparib selectively induced apoptosis and inhibited colony formation in cells lacking BRCA2 or ATM. Moreover, like earlier generation PARP inhibitors, olaparib and veliparib sensitized cells to the topoisomerase I poisons camptothecin and topotecan. Finally, olaparib and veliparib inhibited formation of pADPr in intact cells. In contrast, iniparib exhibited little or no ability to selectively kill HR-deficient cells, sensitize cells to topoisomerase I poisons, or inhibit pADPr formation in situ. In further experiments, iniparib also failed to sensitize cells to cisplatin, gemcitabine, or paclitaxel.
  
  
  CONCLUSIONS
  While iniparib kills normal and neoplastic cells at high (>40 μmol/L) concentrations, its effects are unlikely to reflect PARP inhibition and should not be used to guide decisions about other PARP inhibitors.
authors.affiliation: Department of Molecular Pharmacology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Anand G
authors.initials: AG
authors.lastname: Patel
authors.forename: Silvana B
authors.initials: SB
authors.lastname: De Lorenzo
authors.forename: Karen S
authors.initials: KS
authors.lastname: Flatten
authors.forename: Guy G
authors.initials: GG
authors.lastname: Poirier
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kaufmann
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D059765:Homologous Recombination; D006801:Humans; D051379:Mice; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D001562:Benzimidazoles; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D059004:Topoisomerase I Inhibitors; C521013:veliparib; C090712:iniparib; C531550:olaparib