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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: 5.48). 04/2010; 53(12):4561-84. DOI: 10.1021/jm100012m
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Available from: Dana V Ferraris, Aug 13, 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[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.
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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. "
    [Show abstract] [Hide abstract]
    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.
    Cell 07/2013; 154(2):430-41. DOI:10.1016/j.cell.2013.06.016 · 33.12 Impact Factor
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    • "Other PARPi in preclinical and phase I trial stages include GPI21016 (MGI/Eisai), MK- 4827 (Merck), BMN-673 (Biomarin) and CEP- 9722 (Cephalon). Additional information on these inhibitors can be found in a review by Ferraris [Ferraris, 2010]. "
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    ABSTRACT: The modulation of DNA repair pathways for therapeutic benefit in cancer has now become a reality with the development of poly (ADP-ribose) polymerase inhibitors (PARPi). PARP is involved in single-strand DNA breaks, which in the presence of defective homologous recombination repair lead to double-strand DNA breaks, the most lethal form of DNA damage. These agents therefore may be the drugs of choice for BRCA mutant breast and ovarian cancers. PARPi result in synergistic antitumor effects when combined with cisplatin, temozolomide, topoisomerase inhibitors and ionizing radiation. The indications for PARPi lie beyond BRCA mutations and may include genomic and functional defects in DNA repair and damage response pathways. Several PARPi are in the clinical development phase at this time and, given the recent failure of a phase III clinical trial of iniparib in triple-negative breast cancer, the identification of structural and functional differences between these inhibitors becomes critical. Acquired resistance to PARPi is being noted and represents an important limitation in this field. A concise review of the literature in this field is presented.
    rapeutic Advances in Medical Oncology, The 11/2011; 3(6):257-67. DOI:10.1177/1758834011417039
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