Target Information

Target General Infomation
Target ID
T27325
Former ID
TTDS00079
Target Name
DNA topoisomerase I
Gene Name
TOP1MT
Synonyms
Topoisomerase-I; TOP1MT
Target Type
Successful
Disease Breast cancer [ICD9: 174, 175; ICD10: C50]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Colorectal cancer [ICD9: 153, 154; ICD10: C18-C21]
Lung cancer [ICD9: 162; ICD10: C33-C34]
Ovarian cancer [ICD9: 183; ICD10: C56]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Small-cell lung cancer [ICD9: 162.9; ICD10: C33-C34]
Function
Releases the supercoiling and torsional tension of DNA introduced during duplication of mitochondrial DNA by transiently cleaving and rejoining one strand of the DNA duplex. Introduces a single-strand break via transesterification at a target site in duplex DNA.The scissile phosphodiester is attacked by the catalytic tyrosine of the enzyme, resulting in the formation of a DNA-(3'-phosphotyrosyl)-enzyme intermediate and the expulsion of a 5'-OH DNA strand. The free DNA strand then undergoes passage around the unbroken strand thus removing DNA supercoils. Finally, in the religation step, the DNA 5'-OH attacks the covalent intermediate to expel the active-site tyrosine and restore the DNA phosphodiester backbone (By similarity).
BioChemical Class
DNA topoisomerase
Target Validation
T27325
UniProt ID
Q969P6
EC Number
EC 5.99.1.2
Sequence
MRVVRLLRLRAALTLLGEVPRRPASRGVPGSRRTQKGSGARWEKEKHEDGVKWRQLEHKG
PYFAPPYEPLPDGVRFFYEGRPVRLSVAAEEVATFYGRMLDHEYTTKEVFRKNFFNDWRK
EMAVEEREVIKSLDKCDFTEIHRYFVDKAAARKVLSREEKQKLKEEAEKLQQEFGYCILD
GHQEKIGNFKIEPPGLFRGRGDHPKMGMLKRRITPEDVVINCSRDSKIPEPPAGHQWKEV
RSDNTVTWLAAWTESVQNSIKYIMLNPCSKLKGETAWQKFETARRLRGFVDEIRSQYRAD
WKSREMKTRQRAVALYFIDKLALRAGNEKEDGEAADTVGCCSLRVEHVQLHPEADGCQHV
VEFDFLGKDCIRYYNRVPVEKPVYKNLQLFMENKDPRDDLFDRLTTTSLNKHLQELMDGL
TAKVFRTYNASITLQEQLRALTRAEDSIAAKILSYNRANRVVAILCNHQRATPSTFEKSM
QNLQTKIQAKKEQVAEARAELRRARAEHKAQGDGKSRSVLEKKRRLLEKLQEQLAQLSVQ
ATDKEENKQVALGTSKLNYLDPRISIAWCKRFRVPVEKIYSKTQRERFAWALAMAGEDFE
F
Structure
1A31; 1A35; 1A36; 1EJ9; 1K4S; 1K4T; 1LPQ; 1NH3; 1R49; 1RR8; 1RRJ; 1SC7; 1SEU; 1T8I; 1TL8
Drugs and Mode of Action
Drug(s) Belotecan hydrocholoride Drug Info Approved Small-cell lung cancer [1]
Irinotecan Drug Info Approved Colorectal cancer [2], [3]
Sphingosomal topotecan Drug Info Approved Cancer [4]
Topetecan Drug Info Approved Small-cell lung cancer [5]
Topotecan Drug Info Approved Ovarian cancer [6], [7]
9-Nitrocamptothecin (9-NC) Drug Info Phase 2 Discovery agent [8]
CKD602 Drug Info Phase 2 Cancer [9]
NK-611 Drug Info Discontinued in Phase 2 Solid tumours [10]
Liposomal lurtotecan Drug Info Discontinued in Phase 1 Lung cancer [11]
Datelliptium chloride Drug Info Terminated Breast cancer [12]
Inhibitor (5Z,9Z)-5,9-heptacosadienoic acid Drug Info [13]
10-hydroxycamptothecin Drug Info [14]
3,3'-(4-phenylpyridine-2,6-diyl)diphenol Drug Info [15]
3-(4-phenyl-2,4'-bipyridin-6-yl)phenol Drug Info [15]
3-(4-phenyl-6-(thiophen-2-yl)pyridin-2-yl)-phenol Drug Info [15]
3-(4-phenyl-6-(thiophen-3-yl)pyridin-2-yl)-phenol Drug Info [15]
3-(6-phenyl-2,4'-bipyridin-4-yl)phenol Drug Info [15]
4-(4,6-diphenylpyridin-2-yl)phenol Drug Info [15]
4-(6-phenyl-2,4'-bipyridin-4-yl)phenol Drug Info [15]
4-hydroxysaprothoquinone Drug Info [16]
CHO793076 Drug Info [17]
CKD602 Drug Info [18]
E-758 Drug Info [19]
Homocamptothecins (hCPTs) Drug Info [20]
Liposomal lurtotecan Drug Info [21]
Luteolin Drug Info [22]
NK-611 Drug Info [23]
NSC-341622 Drug Info [24]
ROSETTACIN Drug Info [24]
Topetecan Drug Info [25]
TOPOSTATIN Drug Info [26]
Activator 2,3-Dimethoxybenzo[i]phenanthridines Drug Info [27]
Binder 5-hydroxy-1H-indole-3-acetic acid Drug Info [28]
7-amino-4-hydroxy-2-naphthalenesulfonic acid Drug Info [28]
Dibenzo-p-dioxin-2-carboxylic acid Drug Info [28]
Quinizarin Drug Info [28]
Inducer 9-Nitrocamptothecin (9-NC) Drug Info [29]
KT6006 Drug Info [30]
KT6528 Drug Info [30]
Modulator Belotecan hydrocholoride Drug Info [31], [32]
Datelliptium chloride Drug Info [33]
Irinotecan Drug Info [34]
Sphingosomal topotecan Drug Info [4]
Topotecan Drug Info [34]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
WikiPathways Integrated Pancreatic Cancer Pathway
References
REF 1Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
REF 2New drugs for the treatment of cancer, 1990-2001. Isr Med Assoc J. 2002 Dec;4(12):1124-31.
REF 3(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: 6823).
REF 4Plant-derived compounds in clinical trials. Drug Discov Today. 2008 Feb;13(3-4):161-71.
REF 5FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 020671.
REF 6Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77. Epub 2007 Feb 20.
REF 7(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: 7101).
REF 8ClinicalTrials.gov (NCT00250068) Study of Aerosolized Liposomal 9-Nitro-20 (S)- Camptothecin (L9NC). U.S. National Institutes of Health.
REF 9ClinicalTrials.gov (NCT00430144) Belotecan (CKD-602) in Recurrent or Progressive Carcinoma of Uterine Cervix. U.S. National Institutes of Health.
REF 10Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002418)
REF 11Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010410)
REF 12Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001278)
REF 13J 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.
REF 14Upregulation 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.
REF 15Bioorg 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.
REF 16J Nat Prod. 2002 Jul;65(7):1016-20.Bioactive abietane and seco-abietane diterpenoids from Salvia prionitis.
REF 17Bioorg Med Chem Lett. 2009 Apr 1;19(7):2018-21. Epub 2009 Feb 12.Synthesis of new camptothecin analogs with improved antitumor activities.
REF 18Antitumor 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.
REF 19Lycobetaine acts as a selective topoisomerase IIbeta poison and inhibits the growth of human tumour cells. Br J Cancer. 2001 November; 85(10): 1585-1591.
REF 20Homocamptothecins: potent topoisomerase I inhibitors and promising anticancer drugs. Crit Rev Oncol Hematol. 2003 Jan;45(1):91-108.
REF 21Phase I and pharmacokinetic study of a low-clearance, unilamellar liposomal formulation of lurtotecan, a topoisomerase 1 inhibitor, in patients with advanced leukemia. Cancer. 2004 Apr 1;100(7):1449-58.
REF 22Luteolin, an emerging anti-cancer flavonoid, poisons eukaryotic DNA topoisomerase I. Biochem J. 2002 Sep 1;366(Pt 2):653-61.
REF 23DNA topoisomerase II poisons and inhibitors. Cancer Chemother Biol Response Modif. 1997;17:114-31.
REF 24Bioorg 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.
REF 25Clinical pipeline report, company report or official report of GlaxoSmithKline (2009).
REF 26J Nat Prod. 2001 Feb;64(2):204-7.Isoaurostatin, a novel topoisomerase inhibitor produced by Thermomonospora alba.
REF 272,3-Dimethoxybenzo[i]phenanthridines: topoisomerase I-targeting anticancer agents. Bioorg Med Chem. 2003 Feb 20;11(4):521-8.
REF 28Comparison 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.
REF 29A 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.
REF 30Induction of mammalian DNA topoisomerase I mediated DNA cleavage by antitumor indolocarbazole derivatives. Biochemistry. 1992 Dec 8;31(48):12069-75.
REF 31Belotecan, new camptothecin analogue, is active in patients with small-cell lung cancer: results of a multicenter early phase II study. Ann Oncol. 2008 Jan;19(1):123-7. Epub 2007 Sep 6.
REF 32Impact of natural products on developing new anti-cancer agents. Chem Rev. 2009 Jul;109(7):3012-43.
REF 33Toxicity of the antitumoral drug datelliptium in hepatic cells: Use of models in vitro for the prediction of toxicity in vivo. Toxicol In Vitro. 1992 Jul;6(4):295-302.
REF 34Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.

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