Novel potent inhibitors of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP)
Griffin, R.J.; Pemberton, L.C.; Rhodes, D.; Bleasdale, C.; Bowman, K.; Calvert, A.H.; Curtin, N.J.; Durkacz, B.W.; Newell, D.R.; Porteous, J.K.
Anti-Cancer Drug Design 10(6): 507-514
1995
ISSN/ISBN: 0266-9536 PMID: 7575991 Document Number: 5549
The nuclear eukaryotic enzyme poly(ADP-ribose)polymerase [PARP (EC 2.4.2.30)] catalyses the transfer of the ADP-ribose moiety of nicotinamide adenine dinucleotide (NAD+) to nuclear acceptor proteins, in response to DNA strand-break formation. The protein-bound linear and branched-chain homo-ADP polymers thus formed are implicated in a number of important cellular processes, including DNA repair, cellular differentiation, gene expression and apoptosis. Since poly(ADP-ribosyl)ation occurs as a result of DNA damage induced either by radiation or drugs, inhibitors of the enzyme may enhance the antitumour activity resulting from radiotherapy or cytotoxic drug action by impeding PARP-mediated DNA repair processes. However, extrapolation of the in vitro potentiating activity of currently available PARP inhibitors, which are mainly 3-substituted benzamide derivatives, to the clinic, has been hampered by the lack of potency, selectivity and solubility of these agents. As part of a programme centred on the development of novel resistance-modifying agents for use in cancer chemotherapy, the preliminary results of studies aimed at identifying potent inhibitors of PARP are reported.
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