Inhibitor SourceBook™ Second Edition

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Cell Division/Cell Cycle/Cell Adhesion Poly(ADP-ribose) Polymerase (PARP) and Poly(ADP-ribose) Glycohydrolase (PARG) Inhibitors Poly(ADP-ribosyl)ation (pADPr) is a covalent posttranslational modification process that occurs during DNA repair, replication, and transcription. It is brought about by poly(ADP-ribose)polymerases (PARP), which are activated by breaks in DNA strands. PARPs are a group of Zn 2+ -binding multi-functional enzymes that catalyze the transfer of ADP-ribose (ADPr) units onto protein acceptors to produce linear and/or branched polymers of ADPr. Upon binding to DNA strand breaks, activated PARP cleaves NAD + into nicotinamide and ADP-ribose and polymerizes ADP-ribose onto nuclear acceptor proteins, such as histones and transcription factors. The “classical” 113 kDa type I PARP is the major contributor of the poly(ADP-ribosyl)ating activity in higher eukaryotes. Type II PARP is smaller than the classical zinc-finger-containing PARP and is believed to participate in DNA repair during apoptosis. Type III PARP is a large protein containing ankyrin repeats and a PARP catalytic domain. PARP consists of three domains: a DNA-binding domain (DBD), an automodification domain, and a catalytic domain. The DBD, a 42 kDa N-terminal region, extends from the initiator Met to Thr 373 in human PARP. It contains two zinc fingers and two helix-turn-helix motifs and is rich in basic residues, which are involved in the interaction of the enzyme with DNA. The automodification domain located in the central region, resides between Ala 374 and Leu 525 in human PARP. A BRCT (BRCA1 C-terminus) domain that lies between Ala 384 and Ser 479 and consists of about 95 amino acids is found in several proteins that regulate cell-cycle checkpoints and DNA repair. BRCT domains are protein-protein interaction modules that allow BRCT-motif-containing proteins to establish strong and specific associations. The C-terminal catalytic domain, a 55 kDa segment, spans residues Thr 526 to Trp 1014 in human PARP. The catalytic activity of this fragment is not stimulated by DNA strand breaks. It corresponds only to the basal activity of the native enzyme. The ADPr transferase activity has been confined to a 40 kDa region at the extreme C-terminus of the enzyme, which is referred to as the minimal catalytic domain. This region can catalyze the initiation, elongation, and branching of ADPr polymers independently of the presence of DNA. The deletion of the last 45 amino acids at the C-terminal end of this domain completely abolishes enzyme activity. Residues spanning positions Leu 859 to Tyr 908 in human PARP are well conserved and comprise the “PARP signature” sequence. The extent of poly(ADP-ribosyl)ation is an important determinant of NAD + levels in cells. In normal, undamaged cells, NAD + levels range from 400 to 500 mM. However, PARP activation following DNA damage by radiation or cytotoxic agents reduces NAD + levels to about 100 mM within about 15 minutes. It is believed that during its automodification PARP becomes more charged, since each residue of ADPr adds two negative charges on to the molecule. This establishes an electro-repulsive gradient between the polymers of ADPr which are covalently linked to the enzyme and DNA. When the charge becomes too negative, the reaction reaches a “point of repulsion” and the interaction between PARP and DNA is lost. The poly(ADP-ribosyl)ated PARP molecule is consequently freed from the DNA strand break and its catalytic activity is abolished. Subsequently, poly(ADP-ribose) glycohydrolase (PARG) hydrolyses the polymers present on PARP, thereby allowing it to resume a new cycle of automodification in response to DNA damage. The presence of PARG during PARP automodification restores both its affinity for DNA and its catalytic activity. DNA damage, the single most important factor in the regulation of pADPr reactions, can stimulate the catalytic activity of PARP by about 500-fold. Inhibition of PARP is shown to reduce DNA repair, increase the cytotoxicity of DNA-damaging agents, and enhance apoptosis. The cytotoxicity of PARP inhibitors is due to an increase in the half-life of DNA strand break, which increases genomic instability. PARP cleavage by caspase-3 is considered as an early event in apoptotic cell death. PARP degradation has also been reported during necrosis, although believed to be through a different process. References: Masutani, M., et al. 2003. Genes Chromosomes Cancer 38, 339. Chiarugi, A. 2002. Trends Pharmacol. Sci. 23, 22. Virag. L., and Szabo, C. 2002. Pharmacol. Rev. 54, 375. Burkle, A. 200 . BioEssays 23, 795. Davidovic, L. 200 . Exp. Cell Res. 268, 7. Tong, W.M., et al. 200 . Biochim. Biophys. Acta 1552, 27. DíAmours, D., et al. 999. Biochem. J. 342, 249. Shieh, W.M., et al. 998. J. Biol. Chem. 273, 30069. Mazen, A., et al. 989. Nucleic Acids Res. 17, 4689. Alkhatib, H.M.., et al. 987. Proc. Natl. Acad. Sci. USA 84, 224. More online... www.calbiochem.com/inhibitors/PARP 78 Orders Phone 800 854 34 7 Calbiochem • Inhibitor SourceBook Fax 800 776 0999 Web www.emdbiosciences.com/calbiochem
Calbiochem • Inhibitor SourceBook Cell Division/Cell Cycle/Cell Adhesion Poly(ADP-ribose) Polymerase (PARP) and Poly(ADP-ribose) Glycohydrolase (PARG) Inhibitors Product Cat. No. Comments Size Price ADP-HPD, Dihydrate, Ammonium Salt 3-Aminobenzamide 165350 (3-ABA) 4-Amino- ,8naphthalimide 5-Aminoisoquinolinone, Hydrochloride 118415 [Adenosine 5´-diphosphate (Hydroxymethyl)pyrrolidinediol, NH 4 ] An amino analog of ADP-ribose that acts as a highly potent, noncompetitive, and specific inhibitor of PARG (IC 50 = 20 nM) vs. ADP-ribose (IC 50 = 20 mM). An inhibitor of PARP that has minimal effect on bacterial toxin-mediated ADP-ribosylation. 164585 (4-ANI) A potent inhibitor of poly(ADP-ribose) polymerase (PARP) (IC 50 = 80 nM) that significantly potentiates the cytotoxicity effects of g-irradiation. 164300 [5-AIQ, HCl; 5-Aminoisoquinolin-1(2H)-one, HCl] A cell-permeable, water-soluble analog of isoquinoline that acts as a potent and specific inhibitor of PARP (IC 50 = 240 nM for PARP isolated from calf thymus). Reported to inhibit hydrogen peroxide-induced PARP activity in human cardiac myoblasts (Girardi cells) (IC 50 ~ 0 mM). DPQ 300270 {3,4-Dihydro-5[4-(1-piperindinyl)butoxy]-1(2H)-isoquinoline} A very potent and selective poly(ADP-ribose)polymerase (PARP) inhibitor (IC 50 = 40 nM). EB-47 324473 A cell-permeable, adenosine-substituted, isoindolinone compound that acts as a potent inhibitor of PARP- (IC 50 = 45 nM). 5-Iodo-6-amino- ,2benzopyrone 407850 (INH 2 BP) A lipophilic PARP inhibitor that offers protection against peroxynitrite and hydroxyl radicals in vitro and in vivo. Abrogates peroxynitrite-induced mitochodrial transmembrane potential (Dy m ) reduction. ,5-Isoquinolinediol 419800 [1,5-Dihydroxyisoquinoline; 5-Hydroxy-1(2H)-isoquinoline] A potent inhibitor of poly(ADP-ribose) polymerase (PARP; IC = 390 nM). 50 NU 025 493800 (8-Hydroxy-2-methylquinazoline-4-one) A potent inhibitor of PARP (IC = 400 nM) that potentiates the cytotoxicity of 50 various DNA-active agents, including the DNA-methylating compound MTIC, the DNA strand break-inducing drug temozolomide, topotecan, bleomycin, and ionizing radiation in murine L 2 0 leukemia cells, Chinese hamster ovary cells, and in a variety of human tumor cell lines. PJ34 528150 A potent anti-inflammatory agent and an inhibitor of PARP (EC 50 = 20 nM). Shown to be about 0,000-fold more potent than the prototypical PARP inhibitor, 3-Aminobenzamide (Cat. No. 65350) (EC 50 = 200 mM). TIQ-A 612100 (4H-Thieno[2,3-c]isoquinolin-5-one) A cell-permeable, potent inhibitor of PARP (IC 50 = 450 nM for bovine recombinant PARP- ). Related Products PARP Inhibitor Set Provided as a 5 vial set. Each set contains 00 mg of 3-Aminobenzamide (Cat. No. 65350) and 5 mg each of 5-Iodo-6-amino- ,2-benzopyrone (Cat. No. 407850), ,5-Isoquinolinediol (Cat. No. 4 9800), and NU 025 (Cat. No. 493800), and mg of DPQ (Cat. No. 300270). Cat. No. 528820 1 set $293 PARP Cleavage Detection Kit 60 mg set $496 $ 36 00 mg $35 00 mg $48 mg 5 mg $52 $ 64 mg $76 mg $73 5 mg $57 5 mg $62 5 mg $ 27 mg 5 mg $55 $ 69 mg $79 An assay kit designed to detect poly(ADP-ribose) polymerase (PARP) cleavage by Western blotting. During apoptosis, PARP is cleaved by caspase-3. Cleavage of PARP from the native 6 kDa to 85 kDa is a hallmark of apoptosis. Each kit is provided with a highly specific rabbit polyclonal antibody that detects 6 kDa PARP and the 85 kDa apoptosisrelated cleavage fragment from human, bovine, rat, and mouse. Cat. No. 512729 1 kit $273 Technical Support Phone 800 628 8470 E-mail calbiochem@emdbiosciences.com 79
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Akt (Protein Kinase B) Inhibitors,
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Calmodulin-Dependent Protein Kinase
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Casein Kinase (CK) Inhibitors Casei
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Checkpoint Kinase Inhibitors Eukary
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Cyclin-Dependent Kinase (Cdk) Inhib
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Glycogen Synthase Kinase-3 (GSK-3)
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Glycogen Synthase Kinase Inhibitors
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c-Jun N-Terminal Kinase (JNK/SAP Ki
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Mitogen-Activated Protein (MAP) Kin
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Page 39 and 40: Isozyme Specificities of Selected P
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Page 47 and 48: Protein Tyrosine Kinase (PTK) Inhib
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Page 59 and 60: Rho Kinase (ROCK) Inhibitors, conti
Page 61 and 62: Protein Phosphatase Inhibitors Calb
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Page 65 and 66: Apoptosis Caspase Inhibitors Activa
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Page 73 and 74: DNA Methyltransferase Inhibitors DN
Page 75 and 76: Histone Acetylase and Deacetylase I
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Page 83 and 84: Telomerase Inhibitors, continued Ca
Page 85 and 86: Topoisomerase Related Inhibitors, c
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Page 115 and 116: Proteases Anthrax Lethal Factor (LF
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Protease Inhibitors, continued Calb
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Protease Inhibitors, continued Sele
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Protease Inhibitor Cocktails, conti
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N Animal-Free Protease Inhibitor Co
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Proteasome and Ubiquitination Pathw
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Transmembrane receptors of various
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Angiotensin-Converting Enzyme (ACE)
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ATPase Inhibitors, continued Calbio
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Inhibitors of Glycoprotein Processi
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Heat Shock Protein Inhibitors Heat
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Inhibitors of Mitochondrial Functio
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NF-kB Activation Inhibitors NF-kB,
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NF-kB Activation Inhibitors, contin
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Phosphodiesterase (PDE) Inhibitors
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Plasminogen Activator Inhibitors Ti
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Protein Synthesis Inhibitors, conti
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Sonic Hedgehog Signaling Inhibitors
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Why can’t I make serial dilutions
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Calpastatin, Human, Recombinant, Do
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InSolution Microcystin-LR, Microcys
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RNA Polymerase III Inhibitor ......
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Trademarks CALBIOCHEM®
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