Target Information

Target General Infomation
Target ID
T06273
Former ID
TTDS00191
Target Name
Poly [ADP-ribose] polymerase-1
Gene Name
PARP1
Synonyms
ADPRT; NAD(+) ADP-ribosyltransferase-1; NAD(+)Poly [ADP-ribose] polymerase-1 ADP-ribosyltransferase-1; PARP-1; Poly(ADP-ribose)polymerase-1; Poly[ADP-ribose] synthetase-1; PARP1
Target Type
Successful
Disease Ataxia telangiectasia [ICD10: G11.3]
Brain ischaemia [ICD9: 435, 437; ICD10: G45.9, I67.8]
Cerebrovascular ischaemia [ICD9: 434.91; ICD10: I61-I63]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Cerebrovascular disorders [ICD10: I60-I69]
Inflammatory skin condition [ICD10: L00-L99]
Myocardial infarction [ICD9: 410; ICD10: I21, I22]
Melanoma [ICD9: 172; ICD10: C43]
Ovarian cancer [ICD9: 183; ICD10: C56]
Permanent and transient stroke [ICD9: 434.91, 435.9; ICD10: G45.9, I61-I63]
Recurrent epithelial ovarian or primary peritoneal cancer [ICD10: C78]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Function
Involved in the base excision repair (BER) pathway, by catalyzing the poly(ADP-ribosyl)ation of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism. This modification follows DNA damages and appears as an obligatory step in a detection/signaling pathway leading to the reparation of DNA strand breaks. Mediates the poly(ADP- ribosyl)ation of APLF and CHFR. Positively regulates the transcription of MTUS1 and negatively regulates the transcription of MTUS2/TIP150. With EEF1A1 and TXK, forms a complex that acts as a T-helper 1 (Th1) cell-specific transcription factor and binds the promoter of IFN-gamma to directly regulate its transcription, and is thus involved importantly in Th1 cytokine production. Required for PARP9 and DTX3L recruitment to DNA damage sites. PARP1-dependent PARP9-DTX3L-mediated ubiquitination promotes the rapid and specific recruitment of 53BP1/TP53BP1, UIMC1/RAP80, and BRCA1 to DNA damage sites.
BioChemical Class
Pentosyltransferase
Target Validation
T06273
UniProt ID
P09874
EC Number
EC 2.4.2.30
Sequence
MAESSDKLYRVEYAKSGRASCKKCSESIPKDSLRMAIMVQSPMFDGKVPHWYHFSCFWKV
GHSIRHPDVEVDGFSELRWDDQQKVKKTAEAGGVTGKGQDGIGSKAEKTLGDFAAEYAKS
NRSTCKGCMEKIEKGQVRLSKKMVDPEKPQLGMIDRWYHPGCFVKNREELGFRPEYSASQ
LKGFSLLATEDKEALKKQLPGVKSEGKRKGDEVDGVDEVAKKKSKKEKDKDSKLEKALKA
QNDLIWNIKDELKKVCSTNDLKELLIFNKQQVPSGESAILDRVADGMVFGALLPCEECSG
QLVFKSDAYYCTGDVTAWTKCMVKTQTPNRKEWVTPKEFREISYLKKLKVKKQDRIFPPE
TSASVAATPPPSTASAPAAVNSSASADKPLSNMKILTLGKLSRNKDEVKAMIEKLGGKLT
GTANKASLCISTKKEVEKMNKKMEEVKEANIRVVSEDFLQDVSASTKSLQELFLAHILSP
WGAEVKAEPVEVVAPRGKSGAALSKKSKGQVKEEGINKSEKRMKLTLKGGAAVDPDSGLE
HSAHVLEKGGKVFSATLGLVDIVKGTNSYYKLQLLEDDKENRYWIFRSWGRVGTVIGSNK
LEQMPSKEDAIEHFMKLYEEKTGNAWHSKNFTKYPKKFYPLEIDYGQDEEAVKKLTVNPG
TKSKLPKPVQDLIKMIFDVESMKKAMVEYEIDLQKMPLGKLSKRQIQAAYSILSEVQQAV
SQGSSDSQILDLSNRFYTLIPHDFGMKKPPLLNNADSVQAKVEMLDNLLDIEVAYSLLRG
GSDDSSKDPIDVNYEKLKTDIKVVDRDSEEAEIIRKYVKNTHATTHNAYDLEVIDIFKIE
REGECQRYKPFKQLHNRRLLWHGSRTTNFAGILSQGLRIAPPEAPVTGYMFGKGIYFADM
VSKSANYCHTSQGDPIGLILLGEVALGNMYELKHASHISKLPKGKHSVKGLGKTTPDPSA
NISLDGVDVPLGTGISSGVNDTSLLYNEYIVYDIAQVNLKYLLKLKFNFKTSLW
Drugs and Mode of Action
Drug(s) KU-0058948 Drug Info Approved Ovarian cancer [533123]
Nicotinamide Drug Info Approved Inflammatory skin condition [538965], [551997]
Niraparib Tosylate Drug Info Approved Recurrent epithelial ovarian or primary peritoneal cancer [889446]
Nicaraven Drug Info Phase 3 Cerebrovascular disorders [528516]
AG140699 Drug Info Phase 2 Melanoma [551838]
Intravenous minocycline Drug Info Phase 2 Cerebrovascular ischaemia [531185]
CPH-102 Drug Info Preclinical Cancer [546143]
NU1025 Drug Info Terminated Discovery agent [546083]
PD-128763 Drug Info Terminated Discovery agent [545238]
Inhibitor (E)-N-(4-Phenylthiazol-2-yl) cinnamamide Drug Info [529901]
1,2,3,4,4a,5-hexahydrophenanthridin-6(10bH)-one Drug Info [529901]
1,7,8,9-tetrahydro-1,5-diaza-trindene-4,6-dione Drug Info [527871]
2,3-dihydro-1H-benzo[de]isoquinolin-1-one Drug Info [530584]
2,8-Dimethyl-3H-quinazolin-4-one Drug Info [534774]
2-(2-Chlorophenyl)-2H-indazole-7-carboxamide Drug Info [530485]
2-(3'-Methoxyphenyl) Benzimidazole-4-Carboxamide Drug Info [551374]
2-(3-Chlorophenyl)-2H-indazole-7-carboxamide Drug Info [530485]
2-(3-Piperidin-1-yl-propyl)-3H-quinazolin-4-one Drug Info [527159]
2-(4-Amino-phenyl)-8-hydroxy-3H-quinazolin-4-one Drug Info [534774]
2-(4-Amino-phenyl)-8-methyl-3H-quinazolin-4-one Drug Info [534774]
2-(4-Azido-phenyl)-8-methoxy-3H-quinazolin-4-one Drug Info [534774]
2-(4-Chlorophenyl)-2H-indazole-7-carboxamide Drug Info [530485]
2-(4-Chlorophenyl)-5-Quinoxalinecarboxamide Drug Info [551393]
2-(4-Hydroxy-phenyl)-8-methyl-3H-quinazolin-4-one Drug Info [534774]
2-(4-Methoxy-phenyl)-8-methyl-3H-quinazolin-4-one Drug Info [534774]
2-(4-methoxyphenyl)quinoline-8-carboxamide Drug Info [529894]
2-Benzyl-2H-indazole-7-carboxamide Drug Info [530485]
2-ethylquinoline-8-carboxamide Drug Info [529894]
2-Methylquinoline-8-carboxamide Drug Info [529894]
2-phenyl-2H-benzo[d][1,2,3]triazole-4-carboxamide Drug Info [530485]
2-phenyl-2H-indazole-7-carboxamide Drug Info [530485]
2-phenylpyrazolo-[1,5-a]pyridine-7-carboxamide Drug Info [530485]
2-phenylquinoline-8-carboxamide Drug Info [529894]
2H-Isoquinolin-1-one Drug Info [534774]
3,4-Dihydro-5-Methyl-Isoquinolinone Drug Info [551393]
3-(4-aminophenyl)quinoxaline-5-carboxamide Drug Info [529901]
3-(4-cyanophenyl)quinoxaline-5-carboxamide Drug Info [529901]
3-(4-methoxyphenyl)quinoxaline-5-carboxamide Drug Info [529901]
3-Amino-benzamide Drug Info [534774]
3-aminobenzamide Drug Info [535095]
3-aminobenzo[c][1,5]naphthyridin-6(5H)-one Drug Info [529901]
3-Ethenylquinoline-8-carboxamide Drug Info [529894]
3-Ethylquinoline-8-carboxamide Drug Info [529894]
3-Ethynylquinoline-8-carboxamide Drug Info [529894]
3-Hydroxy-benzamide Drug Info [534774]
3-Methoxybenzamide Drug Info [551393]
3-Methylquinoline-8-carboxamide Drug Info [529894]
3-Morpholin-4-ylmethyl-5H-phenanthridin-6-one Drug Info [527682]
3-Phenylquinoline-8-carboxamide Drug Info [529894]
3-Prop-1-ynylquinoline-8-carboxamide Drug Info [529894]
4-(4-Morpholin-4-yl-butyl)-2H-phthalazin-1-one Drug Info [527682]
4-(5-Morpholin-4-yl-pentyl)-2H-phthalazin-1-one Drug Info [527682]
4-amino-1,8-naphthalimide Drug Info [527871]
4-benzylphthalazin-1(2H)-one Drug Info [529901]
4-methylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione Drug Info [527871]
5-amino-3,4-dihydroisoquinolin-1(2H)-one Drug Info [530584]
5-aminoisoquinolin-1(2H)-one Drug Info [529894]
5-Chloro-2-methyl-3H-quinazolin-4-one Drug Info [527159]
5-methylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione Drug Info [527871]
6-AMINO-BENZO[DE]ISOQUINOLINE-1,3-DIONE Drug Info [551374]
8-Amino-6H,11H-indeno[1,2-c]isoquinolin-5-one Drug Info [527674]
8-Fluoro-6H,11H-indeno[1,2-c]isoquinolin-5-one Drug Info [527674]
8-Hydroxy-2-(4-nitro-phenyl)-3H-quinazolin-4-one Drug Info [534774]
8-Hydroxy-2-phenyl-3H-quinazolin-4-one Drug Info [534774]
8-Methoxy-2-(4-nitro-phenyl)-3H-quinazolin-4-one Drug Info [534774]
8-Methoxy-2-methyl-3H-quinazolin-4-one Drug Info [534774]
8-Methoxy-2-phenyl-3H-quinazolin-4-one Drug Info [534774]
8-Methyl-2-(4-nitro-phenyl)-3H-quinazolin-4-one Drug Info [534774]
8-Methyl-2-phenyl-3H-quinazolin-4-one Drug Info [534774]
8-Nitro-6H,11H-indeno[1,2-c]isoquinolin-5-one Drug Info [527674]
9-Amino-6H,11H-indeno[1,2-c]isoquinolin-5-one Drug Info [527674]
9-Fluoro-6H,11H-indeno[1,2-c]isoquinolin-5-one Drug Info [527674]
A-620223 Drug Info [543709]
AG-014376 Drug Info [527248]
AG140699 Drug Info [536077]
AG14361 Drug Info [526503]
ANG-2684 Drug Info [543709]
ANG-2864 Drug Info [543709]
Benzo[c][1,5]naphthyridin-6(5H)-one Drug Info [529901]
BPI-704001 Drug Info [543709]
BZ3 Drug Info [535762]
BZ5 Drug Info [535762]
BZ6 Drug Info [535762]
Carba-Nicotinamide-Adenine-Dinucleotide Drug Info [551393]
CEP-6800 Drug Info [528503]
CPH-102 Drug Info [543709]
DR2313 Drug Info [536077]
EB-47 Drug Info [536077]
HYDAMTIQ Drug Info [543709]
INO-1002 Drug Info [543709]
KR-33889 Drug Info [543709]
KU-0058948 Drug Info [530062]
KU-58684 Drug Info [529901]
ME0328 Drug Info [532533]
N-(4-Phenylthiazol-2-yl)isonicotinamide Drug Info [529901]
NU1025 Drug Info [551374]
PD-128763 Drug Info [534774]
PJ34 Drug Info [535095]
Pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione Drug Info [527871]
Pyrrolo[3,4-e]indole-1,3(2H,6H)-dione Drug Info [527871]
Quinoline-8-carboxamide Drug Info [529894]
S-070 Drug Info [543709]
S-111 Drug Info [543709]
Thieno-phenanthridin-6-one Drug Info [536077]
TI1 Drug Info [535762]
TI3 Drug Info [535762]
TI4 Drug Info [535762]
Modulator Intravenous minocycline Drug Info [531185]
Nicaraven Drug Info [528516]
Niraparib Tosylate Drug Info [556264]
Binder Nicotinamide Drug Info [537191]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Base excision repair
NF-kappa B signaling pathway
PANTHER Pathway FAS signaling pathway
Pathway Interaction Database Integrin-linked kinase signaling
Caspase Cascade in Apoptosis
Notch-mediated HES/HEY network
Reactome Dual Incision in GG-NER
WikiPathways FAS pathway and Stress induction of HSP regulation
SMAD4 heterotrimer
Nanoparticle triggered regulated necrosis
Corticotropin-releasing hormone
References
Ref 528516Inhibition of poly (ADP-ribose) polymerase as a protective effect of nicaraven in ionizing radiation- and ara-C-induced cell death. Anticancer Res. 2006 Sep-Oct;26(5A):3421-7.
Ref 531185Minocycline protects cardiac myocytes against simulated ischemia-reperfusion injury by inhibiting poly(ADP-ribose) polymerase-1. J Cardiovasc Pharmacol. 2010 Dec;56(6):659-68.
Ref 5331232014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.
Ref 538965(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 1588).
Ref 545238Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002552)
Ref 546083Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006270)
Ref 546143Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006586)
Ref 551838Critical Care Nephrology, Claudio Ronco,Rinaldo Bellomo,John A. Kellum. Page(444).
Ref 551997Drug information of Nicotinamide. United States Environmental Protection Agency. 2015
Ref 889446Drugs@FDA (Edaravone)
Ref 526503Tricyclic benzimidazoles as potent poly(ADP-ribose) polymerase-1 inhibitors. J Med Chem. 2003 Jan 16;46(2):210-3.
Ref 527159J Med Chem. 2004 Aug 12;47(17):4151-4.Rational approaches to discovery of orally active and brain-penetrable quinazolinone inhibitors of poly(ADP-ribose)polymerase.
Ref 527248J Med Chem. 2004 Oct 21;47(22):5467-81.Design, synthesis, and evaluation of 3,4-dihydro-2H-[1,4]diazepino[6,7,1-hi]indol-1-ones as inhibitors of poly(ADP-ribose) polymerase.
Ref 527674J Med Chem. 2005 Aug 11;48(16):5100-3.Discovery of potent poly(ADP-ribose) polymerase-1 inhibitors from the modification of indeno[1,2-c]isoquinolinone.
Ref 527682Bioorg Med Chem Lett. 2005 Oct 1;15(19):4221-5.4-Phenyl-1,2,3,6-tetrahydropyridine, an excellent fragment to improve the potency of PARP-1 inhibitors.
Ref 527871Bioorg Med Chem Lett. 2006 Feb 15;16(4):938-42. Epub 2005 Nov 15.Synthesis and structure-activity relationships of novel poly(ADP-ribose) polymerase-1 inhibitors.
Ref 528503Bioorg Med Chem Lett. 2007 Jan 15;17(2):542-5. Epub 2006 Oct 10.Novel poly(ADP-ribose) polymerase-1 inhibitors.
Ref 528516Inhibition of poly (ADP-ribose) polymerase as a protective effect of nicaraven in ionizing radiation- and ara-C-induced cell death. Anticancer Res. 2006 Sep-Oct;26(5A):3421-7.
Ref 529894J Med Chem. 2009 Feb 12;52(3):868-77.Design, synthesis, and evaluation in vitro of quinoline-8-carboxamides, a new class of poly(adenosine-diphosphate-ribose)polymerase-1 (PARP-1) inhibitor.
Ref 529901J Med Chem. 2009 Feb 12;52(3):718-25.Design, synthesis, and cytoprotective effect of 2-aminothiazole analogues as potent poly(ADP-ribose) polymerase-1 inhibitors.
Ref 530062J Med Chem. 2009 May 14;52(9):3108-11.Structural basis for inhibitor specificity in human poly(ADP-ribose) polymerase-3.
Ref 530485J Med Chem. 2009 Nov 26;52(22):7170-85.Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): a novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors.
Ref 530584Bioorg Med Chem Lett. 2010 Jan 15;20(2):448-52. Epub 2009 Dec 4.Discovery and SAR of novel, potent and selective hexahydrobenzonaphthyridinone inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1).
Ref 531185Minocycline protects cardiac myocytes against simulated ischemia-reperfusion injury by inhibiting poly(ADP-ribose) polymerase-1. J Cardiovasc Pharmacol. 2010 Dec;56(6):659-68.
Ref 532533Chemical probes to study ADP-ribosylation: synthesis and biochemical evaluation of inhibitors of the human ADP-ribosyltransferase ARTD3/PARP3. J Med Chem. 2013 Dec 12;56(23):9556-68.
Ref 534774J Med Chem. 1998 Dec 17;41(26):5247-56.Resistance-modifying agents. 5. Synthesis and biological properties of quinazolinone inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP).
Ref 535095Diabetic endothelial dysfunction: the role of poly(ADP-ribose) polymerase activation. Nat Med. 2001 Jan;7(1):108-13.
Ref 535762Identification of potent nontoxic poly(ADP-Ribose) polymerase-1 inhibitors: chemopotentiation and pharmacological studies. Clin Cancer Res. 2003 Jul;9(7):2711-8.
Ref 536077Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors. Nat Rev Drug Discov. 2005 May;4(5):421-40.
Ref 537191beta-1,2,3-Triazolyl-nucleosides as nicotinamide riboside mimics. Nucleosides Nucleotides Nucleic Acids. 2009 Mar;28(3):238-59.
Ref 543709(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2771).
Ref 551374The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
Ref 551393How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
Ref 556264Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.

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