title: PARP inhibitor development for systemic cancer targeting.
abstract: Poly(ADP-ribose) polymerase 1 (PARP-1) is a DNA-binding enzyme that is activated by DNA breaks, converting them into an intracellular signal via poly(ADP-ribosyl)ation of nuclear proteins. Negatively charged polymers of ADP-ribose (PAR) attached to PARP-1 itself and histones lead to chromatin relaxation, facilitating the access of base excision/single strand break repair proteins and activating these repair enzymes. PARP inhibitors have been developed to investigate the role of PARP-1 in cell biology and to overcome DNA repair-mediated resistance of cancer cells to cytotoxic therapy. Since the early benzamide inhibitors of the 1980s PARP inhibitors, developed through structure-activity relationships and crystal structure-based drug design, that are 1,000 x more potent have been identified. These novel PARP inhibitors have been shown to enhance the antitumour activity of temozolomide (a DNA-methylating agent), topoisomerase poisons and ionising radiation in advanced pre-clinical studies and are now under clinical evaluation. PARP inhibitors can also selectively kill cells and tumours with homozygous defects in the hereditary breast cancer genes, BRCA1 and BRCA2.
authors: Newcastle University, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors: Tomasz
authors: T
authors: Zaremba
authors: Nicola Jane
authors: NJ
authors: Curtin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004249:DNA Damage; D004260:DNA Repair; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors