Article

Evolution of Poly(ADP-ribose) Polymerase-1 (PARP-1) Inhibitors. From Concept to Clinic

Johns Hopkins University Brain Science Institute, 855 N. Wolfe Street, Baltimore, Maryland 21205, USA.
Journal of Medicinal Chemistry (Impact Factor: 5.45). 04/2010; 53(12):4561-84. DOI: 10.1021/jm100012m
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Available from: Dana V Ferraris
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    • "Strikingly , pme-1-deficient worms, either by mutation or RNAi, displayed respectively a 29% or 20% mean lifespan extension (Figure 1H; see Table S1 for statistics). To consolidate these results, we also examined the lifespan of worms upon inhibition of PARP activity with two distinct pan-PARP inhibitors representing different chemical scaffolds (Ferraris, 2010), i.e., AZD2281 (KU59436, olaparib) (Menear et al., 2008), or ABT-888 (veliparib) (Penning et al., 2009). Feeding of worms from eggs until death with different concentrations of PARP inhibitors resulted in a 15%–23% lifespan extension (Figures 1I, 1J, S2A, and S2B; Table S1), with a maximum extension at 100 nM (Figure S2A; Table S2), which is why we chose this concentration for further experiments. "
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    ABSTRACT: NAD[superscript +] is an important cofactor regulating metabolic homeostasis and a rate-limiting substrate for sirtuin deacylases. We show that NAD[superscript +] levels are reduced in aged mice and Caenorhabditis elegans and that decreasing NAD[superscript +] levels results in a further reduction in worm lifespan. Conversely, genetic or pharmacological restoration of NAD[superscript +] prevents age-associated metabolic decline and promotes longevity in worms. These effects are dependent upon the protein deacetylase sir-2.1 and involve the induction of mitonuclear protein imbalance as well as activation of stress signaling via the mitochondrial unfolded protein response (UPR[superscript mt]) and the nuclear translocation and activation of FOXO transcription factor DAF-16. Our data suggest that augmenting mitochondrial stress signaling through the modulation of NAD[superscript +] levels may be a target to improve mitochondrial function and prevent or treat age-associated decline.
    Full-text · Article · Apr 2015
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    • "Strikingly , pme-1-deficient worms, either by mutation or RNAi, displayed respectively a 29% or 20% mean lifespan extension (Figure 1H; see Table S1 for statistics). To consolidate these results, we also examined the lifespan of worms upon inhibition of PARP activity with two distinct pan-PARP inhibitors representing different chemical scaffolds (Ferraris, 2010), i.e., AZD2281 (KU59436, olaparib) (Menear et al., 2008), or ABT-888 (veliparib) (Penning et al., 2009). Feeding of worms from eggs until death with different concentrations of PARP inhibitors resulted in a 15%–23% lifespan extension (Figures 1I, 1J, S2A, and S2B; Table S1), with a maximum extension at 100 nM (Figure S2A; Table S2), which is why we chose this concentration for further experiments. "
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    ABSTRACT: NAD(+) is an important cofactor regulating metabolic homeostasis and a rate-limiting substrate for sirtuin deacylases. We show that NAD(+) levels are reduced in aged mice and Caenorhabditis elegans and that decreasing NAD(+) levels results in a further reduction in worm lifespan. Conversely, genetic or pharmacological restoration of NAD(+) prevents age-associated metabolic decline and promotes longevity in worms. These effects are dependent upon the protein deacetylase sir-2.1 and involve the induction of mitonuclear protein imbalance as well as activation of stress signaling via the mitochondrial unfolded protein response (UPR(mt)) and the nuclear translocation and activation of FOXO transcription factor DAF-16. Our data suggest that augmenting mitochondrial stress signaling through the modulation of NAD(+) levels may be a target to improve mitochondrial function and prevent or treat age-associated decline.
    Full-text · Article · Jul 2013 · Cell
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    • "hPARP-1 has received a lot of interest as a therapeutic target in the pharmaceutical industry after the discovery that the growth of transformed cancer cells deficient in BRCA1/2 can be inhibited by hPARP-1 inhibitors alone [5]. This has accelerated the development of inhibitors and compounds from several companies have entered clinical trials in the past few years [6]. "
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    ABSTRACT: Poly(ADP-ribosylation) is a post-translational covalent modification of proteins catalyzed by a family of enzymes termed poly(ADP-ribose) polymerases (PARPs). In the human genome, 17 different genes have been identified that encode members of the PARP superfamily. Poly (ADP-ribose) metabolism plays a role in a wide range of biological processes. In Trypanosoma cruzi, PARP enzyme appears to play a role in DNA repair mechanisms and may also be involved in controlling the different phases of cell growth. Here we describe the identification of potent inhibitors for T. cruzi PARP with a fluorescence-based activity assay. The inhibitors were also tested on T. cruzi epimastigotes, showing that they reduced ADP-ribose polymer formation in vivo. Notably, the identified inhibitors are able to reduce the growth rate of T. cruzi epimastigotes. The best inhibitor, Olaparib, is effective at nanomolar concentrations, making it an efficient chemical tool for chacterization of ADP-ribose metabolism in T. cruzi. PARP inhibition also decreases drastically the amount of amastigotes but interestingly has no effect on the amount of trypomastigotes in the cell culture. Knocking down human PARP-1 decreases both the amount of amastigotes and trypomastigotes in cell culture, indicating that the effect would be mainly due to inhibition of human PARP-1. The result suggests that the inhibition of PARP could be a potential way to interfere with T. cruzi infection.
    Full-text · Article · Sep 2012 · PLoS ONE
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