Therapeutic Targets Database
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TTD Target ID: TTDS00079

Target Information
NameDNA topoisomerase I    
Type of targetSuccessful target    
SynonymsTopoisomerase-I    
DiseaseBrain tumors
[ICD9: 191, 225.0   ICD10: C71, D33]
[1]
Breast cancer
[ICD9: 174, 175   ICD10: C50]
[2][3]
Cancer, unspecific
[ICD9: 140-229   ICD10: C00-C96]
[4]
Colorectal cancer
[ICD9: 153, 154   ICD10: C18-C21]
[5][2][6]
Esophageal squamous cell cancer
[ICD9: 140-229   ICD10: C00-C96]
[7]
Fungal diseases
[ICD9: 110-118   ICD10: B35-B49]
[8]
Gastric cancer
[ICD9: 151   ICD10: C16]
[2]
Lung cancer
[ICD9: 162   ICD10: C33-C34]
[9][2]
Lymphoblast tumor
[ICD9: 140-199, 210-229   ICD10: C00-C75, C7A, C7B, D10-D36, D3A]
[10]
Ovarian cancer
[ICD9: 183   ICD10: C56]
[2]
Drug(s)Belotecan hydrocholorideApprovedAnticancer (small-cell lung cancer)[11][12][13]
IrinotecanApprovedColorectal Cancer[14][15][5][7][2][9]
Sphingosomal topotecan; Inx-0076ApprovedOncological disease[16][17][18]
TopetecanApprovedSmall cell lung cancer, second-line therapy[19]
TopotecanApprovedOvarian cancer[9][14]
DS-8587Phase IAnti-bacterial
Beta-LapachoneDiscontinued in Phase IICancer[20][21]
BioChemical ClassIsomerases    
EC NumberEC 5.99.1.2
UniProt IDP11387
Q00313
PDB Structure1A31; 1A35; 1A36; 1EJ9; 1K4S; 1K4T; 1LPQ; 1NH3; 1R49; 1RR8; 1RRJ; 1SC7; 1SEU; 1T8I; 1TL8.    
FunctionThe reaction catalyzed by topoisomerases leads to the conversion of one topological isomer of dna to another.    
SequenceMSGDHLHNDSQIEADFRLNDSHKHKDKHKDREHRHKEHKKEKDREKSKHSNSEHKDSEKK HKEKEKTKHKDGSSEKHKDKHKDRDKEKRKEEKVRASGDAKIKKEKENGFSSPPQIKDEP EDDGYFVPPKEDIKPLKRPRDEDDADYKPKKIKTEDTKKEKKRKLEEEEDGKLKKPKNKD KDKKVPEPDNKKKKPKKEEEQKWKWWEEERYPEGIKWKFLEHKGPVFAPPYEPLPENVKF YYDGKVMKLSPKAEEVATFFAKMLDHEYTTKEIFRKNFFKDWRKEMTNEEKNIITNLSKC DFTQMSQYFKAQTEARKQMSKEEKLKIKEENEKLLKEYGFCIMDNHKERIANFKIEPPGL FRGRGNHPKMGMLKRRIMPEDIIINCSKDAKVPSPPPGHKWKEVRHDNKVTWLVSWTENI QGSIKYIMLNPSSRIKGEKDWQKYETARRLKKCVDKIRNQYREDWKSKEMKVRQRAVALY FIDKLALRAGNEKEEGETADTVGCCSLRVEHINLHPELDGQEYVVEFDFLGKDSIRYYNK VPVEKRVFKNLQLFMENKQPEDDLFDRLNTGILNKHLQDLMEGLTAKVFRTYNASITLQQ QLKELTAPDENIPAKILSYNRANRAVAILCNHQRAPPKTFEKSMMNLQTKIDAKKEQLAD ARRDLKSAKADAKVMKDAKTKKVVESKKKAVQRLEEQLMKLEVQATDREENKQIALGTSK LNYLDPRITVAWCKKWGVPIEKIYNKTQREKFAWAIDMADEDYEF
Related US Patent6,420,377
6,465,008
6,677,450
Target ValidationClick to Find Target Validation Information.    
QSAR ModelClick to Find Target QSAR Model.    
Inhibitor (5Z,9Z)-5,9-heptacosadienoic acid[22]
10-hydroxycamptothecin[3]
3,3'- (4-phenylpyridine-2,6-diyl)diphenol[23]
3- (4-phenyl-2,4'-bipyridin-6-yl)phenol[23]
3- (4-phenyl-6-[23]
3- (4-phenyl-6-[23]
3- (6-phenyl-2,4'-bipyridin-4-yl)phenol[23]
4- (4,6-diphenylpyridin-2-yl)phenol[23]
4- (6-phenyl-2,4'-bipyridin-4-yl)phenol[23]
4-hydroxysaprothoquinone[24]
Beta-Lapachone[20][21]
CHO793076[25]
CKD602[26]
Camptothecin[3]
Camptothecin[27]
Homocamptothecins (hCPTs)[28]
Irinotecan[14][15][5][7][2][9]
Luteolin[29]
NSC-341622[30]
ROSETTACIN[30]
SN-38[6]
TAS-103[31]
TOPOSTATIN[32]
Topetecan[19]
Topotecan[9][14]
Activator2,3-Dimethoxybenzo[i]phenanthridines[10]
Inducer9-Nitrocamptothecin (9-NC)[33]
KT6006[34]
KT6528[34]
Ligand5-hydroxy-1H-indole-3-acetic acid[8]
7-amino-4-hydroxy-2-naphthalenesulfonic acid[8]
Dibenzo-p-dioxin-2-carboxylic acid[8]
Quinizarin[8]
Cross References 3D Structure
Related Literature
On-Line Medical Dictionary
Ref 1Novel chemotherapeutic agents for the treatment of brain cancer. Expert Opin Investig Drugs. 2000 Dec;9(12):2815-29. To Reference
Ref 2Chemotherapy with irinotecan (CPT-11), a topoisomerase-I inhibitor, for refractory and relapsed non-Hodgkin's lymphoma. Leuk Lymphoma. 2001 Aug;42(4):577-86. To Reference
Ref 3Upregulation of p21WAF1/CIP1 in human breast cancer cell lines MCF-7 and MDA-MB-468 undergoing apoptosis induced by natural product anticancer drugs 10-hydroxycamptothecin and camptothecin through p53-dependent and independent pathways. Int J Oncol. 1998 Apr;12(4):793-804. To Reference
Ref 4Irinotecan in the treatment of colorectal cancer: clinical overview. J Clin Oncol. 2001 Mar 1;19(5):1501-18. To Reference
Ref 5Augmentation of apoptosis and tumor regression by flavopiridol in the presence of CPT-11 in Hct116 colon cancer monolayers and xenografts. Clin Cancer Res. 2001 Dec;7(12):4209-19. To Reference
Ref 6Cellular pharmacology of the combination of the DNA topoisomerase I inhibitor SN-38 and the diaminocyclohexane platinum derivative oxaliplatin. Clin Cancer Res. 1999 May;5(5):1189-96. To Reference
Ref 7CPT-11 may provide therapeutic efficacy for esophageal squamous cell cancer and the effects correlate with the level of DNA topoisomerase I protein. Jpn J Cancer Res. 2001 Dec;92(12):1335-41. To Reference
Ref 8Comparison of responses of DNA topoisomerase I from Candida albicans and human cells to four new agents which stimulate topoisomerase-dependent DNA nicking. FEMS Microbiol Lett. 1996 May 1;138(2-3):105-11. To Reference
Ref 9New advances in lung cancer chemotherapy: topotecan and the role of topoisomerase I inhibitors. Oncology. 2001;61 Suppl 1:14-24. To Reference
Ref 102,3-Dimethoxybenzo[i]phenanthridines: topoisomerase I-targeting anticancer agents. Bioorg Med Chem. 2003 Feb 20;11(4):521-8. To Reference
Ref 1119422222 To Reference
Ref 12Annual Reviews of Medicinal Chemistry 40 449 To Reference
Ref 1317823384 To Reference
Ref 14Camptothecins in clinical development. Expert Opin Investig Drugs. 2004 Mar;13(3):269-84. To Reference
Ref 15Nat Rev Drug Discov. 2003 Jan;2(1):38-51.Knockouts model the 100 best-selling drugs--will they model the next 100? To Reference
Ref 1618275914 To Reference
Ref 17Giovanella, B.C. et al. (1989) DNA topoisomerase I-targeted chemotherapy of human colon cancer in xenografts. Science 246, 10461048 To Reference
Ref 18(2006) Scrip World Pharmaceutical News 3142, 13 To Reference
Ref 19GSK. Product Development Pipeline. February 2009. To Reference
Ref 20Roche. Product Development Pipeline. July 29 2009. To Reference
Ref 21Roche. News for Roche. 1993. To Reference
Ref 22J Nat Prod. 2002 Nov;65(11):1715-8.Total synthesis and biological evaluation of (5Z,9Z)-5,9-hexadecadienoic acid, an inhibitor of human topoisomerase I. To Reference
Ref 23Bioorg Med Chem. 2010 May 1;18(9):3066-77. Epub 2010 Mar 27.Synthesis, topoisomerase I and II inhibitory activity, cytotoxicity, and structure-activity relationship study of hydroxylated 2,4-diphenyl-6-aryl pyridines. To Reference
Ref 24J Nat Prod. 2002 Jul;65(7):1016-20.Bioactive abietane and seco-abietane diterpenoids from Salvia prionitis. To Reference
Ref 25Bioorg Med Chem Lett. 2009 Apr 1;19(7):2018-21. Epub 2009 Feb 12.Synthesis of new camptothecin analogs with improved antitumor activities. To Reference
Ref 26Antitumor activity of 7-[2-(N-isopropylamino)ethyl]-(20S)-camptothecin, CKD602, as a potent DNA topoisomerase I inhibitor. Arch Pharm Res. 1998 Oct;21(5):581-90. To Reference
Ref 27Wall ME, Wani MC: Camptothecin and taxol: from discovery to clinic. J Ethnopharmacol. 1996 Apr;51(1-3):239-53; discussion 253-4. To Reference
Ref 28Homocamptothecins: potent topoisomerase I inhibitors and promising anticancer drugs. Crit Rev Oncol Hematol. 2003 Jan;45(1):91-108. To Reference
Ref 29Luteolin, an emerging anti-cancer flavonoid, poisons eukaryotic DNA topoisomerase I. Biochem J. 2002 Sep 1;366(Pt 2):653-61. To Reference
Ref 30Bioorg Med Chem. 2009 Oct 15;17(20):7145-55. Epub 2009 Sep 6.Synthesis and biological evaluation of 14-(aminoalkyl-aminomethyl)aromathecins as topoisomerase I inhibitors: investigating the hypothesis of shared structure-activity relationships. To Reference
Ref 31Self-association and unique DNA binding properties of the anti-cancer agent TAS-103, a dual inhibitor of topoisomerases I and II. Biochim Biophys Acta. 2002 Jul 18;1587(2-3):155-63. To Reference
Ref 32J Nat Prod. 2001 Feb;64(2):204-7.Isoaurostatin, a novel topoisomerase inhibitor produced by Thermomonospora alba. To Reference
Ref 33A Phase I study of 9-nitrocamptothecin given concurrently with capecitabine in patients with refractory, metastatic solid tumors. Cancer. 2003 Jan 1;97(1):148-54. To Reference
Ref 34Induction of mammalian DNA topoisomerase I mediated DNA cleavage by antitumor indolocarbazole derivatives. Biochemistry. 1992 Dec 8;31(48):12069-75. To Reference



 

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