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  • Review Article
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Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors

Nature Reviews Drug Discovery volume 4, pages 421–440 (2005)Cite this article

Key Points

  • Poly(ADP-ribose) polymerases (PARPs) are involved a number of cellular processes, including DNA repair, the regulation of transcription, apoptosis and necrosis.

  • PARP activation initiates an energy-consuming inefficient cellular metabolic cycle; this leads to cellular and mitochondrial dysfunction, and promotes the functional impairment of the affected cells, which culminates in cell necrosis.

  • PARP activation is involved in a range of disorders, including various forms of reperfusion injury, inflammation and cardiovascular diseases. PARP inhibitors have been tested in disease models for these conditions, and also investigated for their ability to suppress DNA repair and to promote apoptosis in cells that are treated with certain anticancer agents.

  • Many classes of compounds have been shown to inhibit the catalytic activity of PARP. Moreover, some of these compounds have now successfully progressed through the preclinical efficacy and safety stages of drug development, and have entered human clinical testing.

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.

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Figure 1: Structure of poly(ADP-ribose) polymerase-1 (PARP1).
Figure 2: Activation and inactivation of poly(ADP-ribose) polymerase (PARP): interactions with specific signal-transduction pathways.
Figure 3: Pathways involved in promoting cellular necrosis in response to massive poly(ADP-ribose) polymerase (PARP) activation in oxidatively/nitrosatively injured cells.
Figure 4: Poly (ADP-ribose) polymerase (PARP) and myocardial infarction.
Figure 5: Intensity of DNA-damaging stimuli determines the fate of cells: survival, apoptosis or necrosis.
Figure 6: Pathophysiological triggers of poly(ADP-ribose) polymerase (PARP) activation and interacting pathways of injury.
Figure 7: Schematic representation of the binding of NAD+ to poly(ADP-ribose) polymerase (PARP) protein and the catalytic mechanism of PARP1.
Figure 8: Structures of representative classes of poly(ADP-ribose) polymerase (PARP) inhibitors derived from the classical PARP scaffolds (benzamide or cyclic lactams).
Figure 9: Further poly(ADP-ribose) polymerase (PARP) inhibitors.
Figure 10: PARP inhibition restores tumour-cell sensitivity to temozolomide.

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Acknowledgements

Work in the area of PARP and the pathogenesis of various diseases was supported by grants from the US National Institutes of Health to C.S. and P.J. The authors thank G. Graziani of the University of Rome for helpful discussions.

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Authors and Affiliations

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

    Prakash Jagtap

  2. Department of Human Physiology, Semmelweis University Medical School, Budapest, Hungary

    Csaba Szabó

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  1. Prakash Jagtap
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  2. Csaba Szabó
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Correspondence to Csaba Szabó.

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C.S. and P.G. have the following competing interest: stock (C.S.), stock options (P.J), employment (C.S. and P.J.), board of directors (C.S.) and patents (C.S. and P.J.).

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DATABASES

Entrez Gene

ATF2

ICAM1

IL-6

PARP1

PARP2

TNF-α

WRN

XRCC1

OMIM

atherosclerosis

Parkinson disease

FURTHER INFORMATION

Inotek Pharmaceuticals

Northern Institute for Cancer Research

Glossary

ZINC FINGER

Protein module in which conserved cysteine or histidine residues coordinate a zinc atom. Some zinc-finger regions bind specific DNA sequences.

NUCLEOSOME

A packing unit for DNA within the cell nucleus, which gives the chromatin a 'beads-on-a-string' structure, in which the 'beads' consist of complexes of nuclear proteins (histones) and DNA, and the 'string' consists of DNA only. A histone octamer forms a core around which the double-stranded DNA helix is wound twice.

PHARMACOPHORE

The ensemble of steric and electronic features that is necessary to ensure optimal interactions with a specific biological target structure and to trigger (or to block) its biological response.

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Jagtap, P., Szabó, C. Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors. Nat Rev Drug Discov 4, 421–440 (2005). https://doi.org/10.1038/nrd1718

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