Therapeutic Targets Database
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TTD Target ID: TTDS00191

Target Information
NamePoly [ADP-ribose] polymerase-1    
Type of targetSuccessful target    
SynonymsADPRT    
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    
DiseaseAsthma
[ICD9: 493   ICD10: J45]
[1]
Cancer, unspecific
[ICD9: 140-229   ICD10: C00-C96]
[2]
Chronic obstructive pulmonary disease
[ICD9: 490-492, 494-496   ICD10: J40-J44, J47]
[1]
Diabetic cardiovascular dysfunction
[ICD9: 250   ICD10: E08-E13]
[3]
Diabetic endothelial dysfunction
[ICD9: 250   ICD10: E08-E13]
[4]
Multiple sclerosis
[ICD9: 340   ICD10: G35]
[5]
Traumatic brain injury
[ICD9: 800, 801, 803, 804, 850-854   ICD10: S06]
[6]
Tumors
[ICD9: 140-199, 210-229   ICD10: C00-C75, C7A, C7B, D10-D36, D3A]
[7]
Drug(s)NicotinamideApprovedInflammatory skin conditions[8]
AG-14699Phase IICancer[9]
AG140699Phase IIMalignant melanoma[10]
BSI-201Phase IITriple Negative Breast Cancer[11]
CEP-9722Phase IINSCLC (combination therapy) (see also lymphoma)
E7016(US) PIIMelanoma
INO-1001Phase IIMyocardial infarction, Cardiovascular Disorders[12][13][14][10]
KU-0059436Phase IIGastric Cancer; Breast Cancer; Ovarian Cancer[15][16][17]
OlaparibPhase IIBreast/ovarian cancer[18]
BMN-673Phase I/IISolid Tumors
INO-1001Phase I/IIBrain Cancer[12][13][14][10]
ABT-767Phase ISolid Tumors
BMN-673Phase IHematological malignancies
CEP-9722Phase IMantle cell lymphoma
CEP-9722Phase IMantle cell lymphoma (combination
KU-0059436Phase INeoplasm Metastasis; Solid Tumors[15][16][17]
MK-4827Phase ICancer; Solid Tumors[19][20]
MP-124Phase IStroke
BioChemical ClassGlycosyltransferases    
EC NumberEC 2.4.2.30
PathwayBase excision repair
UniProt IDP09874
PDB Structure1UK0; 1UK1; 1WOK; 2COK; 2CR9; 2CS2; 2DMJ; 2JVN; 2L30; 2L31; 2RCW; 2RD6; 2RIQ; 3GJW; 3GN7; 3L3L; 3L3M; 3OD8; 3ODA; 3ODC; 3ODE; 4AV1; 4DQY; 4HHY; 4HHZ.    
FunctionInvolved in the base excision repair (ber) pathway, by catalysing 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.    
SequenceMAESSDKLYRVEYAKSGRASCKKCSESIPKDSLRMAIMVQSPMFDGKVPHWYHFSCFWKV GHSIRHPDVEVDGFSELRWDDQQKVKKTAEAGGVTGKGQDGIGSKAEKTLGDFAAEYAKS NRSTCKGCMEKIEKGQVRLSKKMVDPEKPQLGMIDRWYHPGCFVKNREELGFRPEYSASQ LKGFSLLATEDKEALKKQLPGVKSEGKRKGDEVDGVDEVAKKKSKKEKDKDSKLEKALKA QNDLIWNIKDELKKVCSTNDLKELLIFNKQQVPSGESAILDRVADGMVFGALLPCEECSG QLVFKSDAYYCTGDVTAWTKCMVKTQTPNRKEWVTPKEFREISYLKKLKVKKQDRIFPPE TSASVAATPPPSTASAPAAVNSSASADKPLSNMKILTLGKLSRNKDEVKAMIEKLGGKLT GTANKASLCISTKKEVEKMNKKMEEVKEANIRVVSEDFLQDVSASTKSLQELFLAHILSP WGAEVKAEPVEVVAPRGKSGAALSKKSKGQVKEEGINKSEKRMKLTLKGGAAVDPDSGLE HSAHVLEKGGKVFSATLGLVDIVKGTNSYYKLQLLEDDKENRYWIFRSWGRVGTVIGSNK LEQMPSKEDAIEHFMKLYEEKTGNAWHSKNFTKYPKKFYPLEIDYGQDEEAVKKLTVNPG TKSKLPKPVQDLIKMIFDVESMKKAMVEYEIDLQKMPLGKLSKRQIQAAYSILSEVQQAV SQGSSDSQILDLSNRFYTLIPHDFGMKKPPLLNNADSVQAKVEMLDNLLDIEVAYSLLRG GSDDSSKDPIDVNYEKLKTDIKVVDRDSEEAEIIRKYVKNTHATTHNAYDLEVIDIFKIE REGECQRYKPFKQLHNRRLLWHGSRTTNFAGILSQGLRIAPPEAPVTGYMFGKGIYFADM VSKSANYCHTSQGDPIGLILLGEVALGNMYELKHASHISKLPKGKHSVKGLGKTTPDPSA NISLDGVDVPLGTGISSGVNDTSLLYNEYIVYDIAQVNLKYLLKLKFNFKTSLW
Related US Patent6,444,676
6,448,271
6,495,541
6,548,494
Target ValidationClick to Find Target Validation Information.    
Inhibitor (E)-N-[21]
1,2,3,4,4a,5-hexahydrophenanthridin-6 (10bH)-one[21]
1,7,8,9-tetrahydro-1,5-diaza-trindene-4,6-dione[22]
2,3-dihydro-1H-benzo[de]isoquinolin-1-one[23]
2,8-Dimethyl-3H-quinazolin-4-one[24]
2- (2-Chlorophenyl)-2H-indazole-7-carboxamide[25]
2- (3'-Methoxyphenyl) Benzimidazole-4-Carboxamide[26]
2- (3-Chlorophenyl)-2H-indazole-7-carboxamide[25]
2- (3-Piperidin-1-yl-propyl)-3H-quinazolin-4-one[27]
2- (4-Amino-phenyl)-8-hydroxy-3H-quinazolin-4-one[24]
2- (4-Amino-phenyl)-8-methyl-3H-quinazolin-4-one[24]
2- (4-Azido-phenyl)-8-methoxy-3H-quinazolin-4-one[24]
2- (4-Chlorophenyl)-2H-indazole-7-carboxamide[25]
2- (4-Chlorophenyl)-5-Quinoxalinecarboxamide[28]
2- (4-Hydroxy-phenyl)-8-methyl-3H-quinazolin-4-one[24]
2- (4-Methoxy-phenyl)-8-methyl-3H-quinazolin-4-one[24]
2- (4-methoxyphenyl)quinoline-8-carboxamide[29]
2-Benzyl-2H-indazole-7-carboxamide[25]
2-Methylquinoline-8-carboxamide[29]
2-ethylquinoline-8-carboxamide[29]
2-phenyl-2H-benzo[d][1,2,3]triazole-4-carboxamide[25]
2-phenyl-2H-indazole-7-carboxamide[25]
2-phenylpyrazolo-[1,5-a]pyridine-7-carboxamide[25]
2-phenylquinoline-8-carboxamide[29]
2H-Isoquinolin-1-one[24]
3,4-Dihydro-5-Methyl-Isoquinolinone[28]
3- (4-aminophenyl)quinoxaline-5-carboxamide[21]
3- (4-cyanophenyl)quinoxaline-5-carboxamide[21]
3- (4-methoxyphenyl)quinoxaline-5-carboxamide[21]
3-Amino-benzamide[24]
3-Ethenylquinoline-8-carboxamide[29]
3-Ethylquinoline-8-carboxamide[29]
3-Ethynylquinoline-8-carboxamide[29]
3-Hydroxy-benzamide[24]
3-Methoxybenzamide[28]
3-Methylquinoline-8-carboxamide[29]
3-Morpholin-4-ylmethyl-5H-phenanthridin-6-one[30]
3-Phenylquinoline-8-carboxamide[29]
3-Prop-1-ynylquinoline-8-carboxamide[29]
3-aminobenzamide[4]
3-aminobenzo[c][1,5]naphthyridin-6 (5H)-one[21]
4- (4-Morpholin-4-yl-butyl)-2H-phthalazin-1-one[30]
4- (5-Morpholin-4-yl-pentyl)-2H-phthalazin-1-one[30]
4-amino-1,8-naphthalimide[22]
4-benzylphthalazin-1 (2H)-one[21]
4-methylpyrrolo[3,4-c]carbazole-1,3 (2H,6H)-dione[22]
5-Chloro-2-methyl-3H-quinazolin-4-one[27]
5-amino-3,4-dihydroisoquinolin-1 (2H)-one[23]
5-aminoisoquinolin-1 (2H)-one[29]
5-methylpyrrolo[3,4-c]carbazole-1,3 (2H,6H)-dione[22]
6-AMINO-BENZO[DE]ISOQUINOLINE-1,3-DIONE[26]
8-Amino-6H,11H-indeno[1,2-c]isoquinolin-5-one[31]
8-Fluoro-6H,11H-indeno[1,2-c]isoquinolin-5-one[31]
8-Hydroxy-2- (4-nitro-phenyl)-3H-quinazolin-4-one[24]
8-Hydroxy-2-phenyl-3H-quinazolin-4-one[24]
8-Methoxy-2- (4-nitro-phenyl)-3H-quinazolin-4-one[24]
8-Methoxy-2-methyl-3H-quinazolin-4-one[24]
8-Methoxy-2-phenyl-3H-quinazolin-4-one[24]
8-Methyl-2- (4-nitro-phenyl)-3H-quinazolin-4-one[24]
8-Methyl-2-phenyl-3H-quinazolin-4-one[24]
8-Nitro-6H,11H-indeno[1,2-c]isoquinolin-5-one[31]
9-Amino-6H,11H-indeno[1,2-c]isoquinolin-5-one[31]
9-Fluoro-6H,11H-indeno[1,2-c]isoquinolin-5-one[31]
ABT-888[32]
AG-014376[33]
AG-14699[9]
AG140699[10]
AZD-2281[17]
BSI-201[11]
BZ3[2]
BZ5[2]
BZ6[2]
CEP-6800[34]
Carba-Nicotinamide-Adenine-Dinucleotide[28]
DR2313[10]
EB-47[10]
INO-1001[12][13][14][10]
KU-0058948[35]
KU-0059436[15][16][17]
KU-58684[21]
MK-4827[19][20]
N- (4-Phenylthiazol-2-yl)isonicotinamide[21]
NU-1025[24]
NU1025[26]
Olaparib[18]
PD-128763[24]
PJ34[4]
Quinoline-8-carboxamide[29]
TI1[2]
TI3[2]
TI4[2]
Thieno-phenanthridin-6-one[10]
benzo[c][1,5]naphthyridin-6 (5H)-one[21]
pyrrolo[3,4-c]carbazole-1,3 (2H,6H)-dione[22]
pyrrolo[3,4-e]indole-1,3 (2H,6H)-dione[22]
BinderNicotinamide[8]
Nicotinamide[28]
Cross References 3D Structure
Related Literature
On-Line Medical Dictionary
Ref 1Gene knockout or pharmacological inhibition of poly(ADP-ribose) polymerase-1 prevents lung inflammation in a murine model of asthma. Am J Respir Cell Mol Biol. 2003 Mar;28(3):322-9. To Reference
Ref 2Identification of potent nontoxic poly(ADP-Ribose) polymerase-1 inhibitors: chemopotentiation and pharmacological studies. Clin Cancer Res. 2003 Jul;9(7):2711-8. To Reference
Ref 3PARP as a Drug Target for the Therapy of Diabetic Cardiovascular Dysfunction. Drug News Perspect. 2002 May;15(4):197-205. To Reference
Ref 4Diabetic endothelial dysfunction: the role of poly(ADP-ribose) polymerase activation. Nat Med. 2001 Jan;7(1):108-13. To Reference
Ref 5Activation of microglial poly(ADP-ribose)-polymerase-1 by cholesterol breakdown products during neuroinflammation: a link between demyelination and neuronal damage. J Exp Med. 2003 Dec 1;198(11):1729-40. To Reference
Ref 6Deleterious poly(ADP-ribose)polymerase-1 pathway activation in traumatic brain injury in rat. Brain Res. 2003 Oct 31;989(1):58-66. To Reference
Ref 7Potential clinical applications of poly(ADP-ribose) polymerase (PARP) inhibitors. Pharmacol Res. 2002 Feb;45(2):73-85. To Reference
Ref 8beta-1,2,3-Triazolyl-nucleosides as nicotinamide riboside mimics. Nucleosides Nucleotides Nucleic Acids. 2009 Mar;28(3):238-59. To Reference
Ref 9Pfizer. Product Development Pipeline. March 31 2009. To Reference
Ref 10Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors. Nat Rev Drug Discov. 2005 May;4(5):421-40. To Reference
Ref 11Pharma & Vaccines. Product Development Pipeline. April 29 2009. To Reference
Ref 12A phase IB trial of intravenous INO-1001 plus oral temozolomide in subjects with unresectable stage-III or IV melanoma. Cancer Invest. 2009 Aug;27(7):756-63. To Reference
Ref 13J Thromb Thrombolysis. 2009 May;27(4):359-64. Epub 2008 Jun 6.A randomized, placebo-controlled trial to evaluate the tolerability, safety, pharmacokinetics, and pharmacodynamics of a potent inhibitor of poly(ADP-ribose) polymerase (INO-1001) in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: results of the TIMI 37 trial. To Reference
Ref 14Poly (ADP) ribose synthetase inhibition in alveolar macrophages undergoing hypoxia and reoxygenation. Exp Mol Pathol. 2008 Apr;84(2):141-4. Epub 2007 Dec 7. To Reference
Ref 15High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17079-84. Epub 2008 Oct 29. To Reference
Ref 16Int J Radiat Oncol Biol Phys. 2008 Nov 15;72(4):1188-97.Replication-dependent radiosensitization of human glioma cells by inhibition of poly(ADP-Ribose) polymerase: mechanisms and therapeutic potential. To Reference
Ref 17J Med Chem. 2008 Oct 23;51(20):6581-91. Epub 2008 Sep 19.4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1. To Reference
Ref 18AstraZeneca. Product Development Pipeline. January 29 2009. To Reference
Ref 19Merck. Product Development Pipeline. July 15 2009. To Reference
Ref 20Merck. Report of Merck. April 2009. To Reference
Ref 21J 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. To Reference
Ref 22Bioorg 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. To Reference
Ref 23Bioorg 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). To Reference
Ref 24J 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). To Reference
Ref 25J 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. To Reference
Ref 26Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. To Reference
Ref 27J 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. To Reference
Ref 28Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. To Reference
Ref 29J 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. To Reference
Ref 30Bioorg 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. To Reference
Ref 31J 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. To Reference
Ref 32J Med Chem. 2009 Jan 22;52(2):514-23.Discovery of the Poly(ADP-ribose) polymerase (PARP) inhibitor 2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide (ABT-888) for the treatment of cancer. To Reference
Ref 33J 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. To Reference
Ref 34Bioorg Med Chem Lett. 2007 Jan 15;17(2):542-5. Epub 2006 Oct 10.Novel poly(ADP-ribose) polymerase-1 inhibitors. To Reference
Ref 35J Med Chem. 2009 May 14;52(9):3108-11.Structural basis for inhibitor specificity in human poly(ADP-ribose) polymerase-3. To Reference



 

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Professor in Department of Pharmacy
National University of Singapore, Singapore


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