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Advances in using PARP inhibitors to treat cancer

Shivaani Kummar1, Alice Chen1, Ralph E Parchment2, Robert J Kinders2, Jay Ji2, Joseph E Tomaszewski1 and James H Doroshow13*

Author Affiliations

1 Division of Cancer Treatment and Diagnosis, Bldg. 31, Room 3A-44, 31 Center Drive, National Cancer Institute, Bethesda, MD, 20892, USA

2 Applied/Developmental Research Directorate, Science Applications International Corporation-Frederick, Inc., Bldg. 431, 1050 Boyles St., National Cancer Institute at Frederick, Frederick, MD, 21702 USA

3 Center for Cancer Research, Bldg. 37, Room 1052, 37 Convent Drive, National Cancer Institute, Bethesda, MD, 20892 USA

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BMC Medicine 2012, 10:25  doi:10.1186/1741-7015-10-25

Published: 9 March 2012

Additional files

Additional File 1:

Early phase clinical trials with PARP inhibitors. A table listing clinical trials of PARP inhibitors currently in development in early phase clinical trials.

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Additional File 2:

Clinical trials with PARP inhibitors in defined diseases. A table listing clinical trials of PARP inhibitors currently in development in specified cancers.

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Additional File 3:

Structural and functional characteristics of PARP1. A: Poly(ADP-ribose) polymerase 1 (PARP1) is shown with its DNA-binding (DBD), automodification (AD) and catalytic domains. The PARP signature sequence (yellow box within the catalytic domain) comprises the sequence most conserved among PARPs. Crucial residues for nicotinamide adenine dinucleotide (NAD+) binding (histidine; H and tyrosine; Y) and for polymerase activity (glutamic acid; E) are indicated. B: Consequences of PARP1 activation by DNA damage. Although not shown to simplify the scheme, PARP1 is active in a homodimeric form. PARP1 detects DNA damage through its DBD. This activates PARP1 to synthesize poly(ADP) ribose (pADPr; yellow beads) on acceptor proteins, including histones and PARP1. Owing to the dense negative charge of pADPr, PARP1 loses affinity for DNA, allowing the recruitment of repair proteins by pADPr to the damaged DNA (blue and purple circles). Poly(ADP-ribose) glycohydrolase (PARG) and possibly ADP-ribose hydrolase 3 (ARH3) hydrolyse pADPr into ADP-ribose molecules and free pADPr. ADP-ribose is further metabolized by the pyrophosphohydrolase NUDiX enzymes into AMP, raising AMP:ATP ratios, which in turn activate the metabolic sensor AMP-activated protein kinase (AMPK). NAD+ is replenished by the enzymatic conversion of nicotinamide into NAD+ at the expense of phosphoribosylpyrophosphate (PRPP) and ATP. Examples of proteins non-covalently (pADPr-binding proteins) or covalently poly(ADP-ribosyl)ated are shown with the functional consequences of modification. It is important to note that many potential protein acceptors of pADPr remain to be identified owing to the difficulty of purifying pADPr-binding proteins in vivo. PARP inhibitors prevent the synthesis of pADPr and hinder subsequent downstream repair processes, lengthening the lifetime of DNA lesions. ATM, ataxia telangiectasia-mutated; BER, base excision repair; BRCT, BRCA1 carboxy-terminal repeat motif; DNA-PKcs, DNA-protein kinase catalytic subunit; DSB, double-strand break; HR, homologous recombination; NHEJ, non-homologous end joining; NLS, nuclear localization signal; PPi, inorganic pyrophosphate; SSB, single-strand break; Zn, zinc finger. Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Cancer [2], copyright (2010).

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