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PARP inhibitor development for systemic cancer targeting

Lookup NU author(s): Tomasz Zaremba, Professor Nicola CurtinORCiD


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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. © 2007 Bentham Science Publishers Ltd.

Publication metadata

Author(s): Zaremba T, Curtin NJ

Publication type: Review

Publication status: Published

Journal: Anti-Cancer Agents in Medicinal Chemistry

Year: 2007

Volume: 7

Issue: 5

Pages: 515-523

ISSN (print): 1871-5206

ISSN (electronic): 1875-5992

PubMed id: 17896912