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Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

PARP Inhibitor Development for Systemic Cancer Targeting

Author(s): Tomasz Zaremba and Nicola Jane Curtin

Volume 7, Issue 5, 2007

Page: [515 - 523] Pages: 9

DOI: 10.2174/187152007781668715

Price: $65


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 1,000x 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.

Keywords: Base excision repair/single strand break repair, Poly(ADP-ribose) polymerase-1 (PARP-1), PARP inhibitors

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