PARP Inhibitor Development for Systemic Cancer Targeting

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


Volume 16, 12 Issues, 2016


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Anti-Cancer Agents in Medicinal Chemistry

Formerly: Current Medicinal Chemistry - Anti-Cancer Agents

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  • 27th of 59 in Chemistry, Medicinal

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Editor-in-Chief:
Michelle Prudhomme
Universite Blaise Pascal - C.N.R.S
Aubiere Cedex
France


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PARP Inhibitor Development for Systemic Cancer Targeting



Anti-Cancer Agents in Medicinal Chemistry, 7(5): 515-523.

Author(s): Tomasz Zaremba and Nicola Jane Curtin.

Affiliation: Newcastle University,Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.

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 1,000x 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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Article Details

Volume: 7
Issue Number: 5
First Page: 515
Last Page: 523
Page Count: 9
DOI: 10.2174/187152007781668715
Price: $58
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