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Nat Rev Drug Discov. 2005 May;4(5):421-40.

Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors.

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1
Inotek Pharmaceuticals Corp., Suite 419E, 100 Cummings Center, Beverly, Massachusetts 01915, USA.

Abstract

Poly(ADP-ribose) polymerases (PARPs) are involved in the regulation of many cellular functions. Three consequences of the activation of PARP1, which is the main isoform of the PARP family, are particularly important for drug development: first, its role in DNA repair; second, its capacity to deplete cellular energetic pools, which culminates in cell dysfunction and necrosis; and third, its capacity to promote the transcription of pro-inflammatory genes. Consequently, pharmacological inhibitors of PARP have the potential to enhance the cytotoxicity of certain DNA-damaging anticancer drugs, reduce parenchymal cell necrosis (for example, in stroke or myocardial infarction) and downregulate multiple simultaneous pathways of inflammation and tissue injury (for example, in circulatory shock, colitis or diabetic complications). The first ultrapotent novel PARP inhibitors have now entered human clinical trials. This article presents an overview of the principal pathophysiological pathways and mechanisms that are governed by PARP, followed by the main structures and therapeutic actions of various classes of novel PARP inhibitors.

PMID:
15864271
DOI:
10.1038/nrd1718
[Indexed for MEDLINE]
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