PARP Inhibitors and Cancer Therapy

The compellit evidence for the role of PARP in the cellular reaction to genotoxic stress has provided an impetus for the development of inhibitors both as a tool to determine the function of PARP and as potential therapeutic agents for use in combination with DNA-damagjt therapies. Knowlet e of the catalytic mechanism of the enzyme is important for the development of inhibitors. PARP catalyses the cleav of its substrate, NAD at the nicotinamide-ribose bond with polymerisation of the ADP-ribose moiety and release of nicotinamide (F. 1). Nicotinamide is itself a weak inhibitor of the reaction and most PARP inhibitors contain the nicotinamide pharmacophore. The earliest inhibitors were simple analogues of nicotinamide— the benzamides (Fig. 2) 

Pofy(ADP-Ribosyl)ation, edited by Alexander Biirkle. 2006 Landes Bioscience and Springer Science+Business Media. 

2-(4-hydroxyphenyl)benzimida2oIe-4-carboxamide, NU1085 (F. 5) which demonstrated gpod chemosensitizing activity in cell cultures at a concentration of 10 

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Curtin NJ (2006) PARP inhibitors and cancer therapy. In Biirlde A (ed) Poly(ADP-Ribosyl)ation. Landes Bioscience, Georgetown, pp218—233... 

PARP-1 inhibitor with the specificity and in vivo activity to enhance chemotherapy and radiation therapy of human cancer (Calabrese et al, 2004). GR205171 has the most potent anti-emetic activity of any tachykinin NKl receptor antagonist described to date. The compound is orally active in the ferret and dog, long-lasting, and warrants further investigation as a potential broad-spectrum anti-emetic agent (Gardner et al, 1996). 

Curtin NJ, Gol ng BT, Griffin RJ et al. New PARP inhibitors for chemr>- and radio-therapy of cancer. In deMurcia G, Shall S, eds. From DNA Damage and Stress S talling to Cell Death Poly ADP-Ribosylation Reactions. Oxford, New York Oxford University Press, 2000 177-206. 

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