Target Information
Target General Infomation | |||||
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Target ID |
T27325
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Former ID |
TTDS00079
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Target Name |
DNA topoisomerase I
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Gene Name |
TOP1MT
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Synonyms |
Topoisomerase-I; TOP1MT
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Target Type |
Successful
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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).
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BioChemical Class |
DNA topoisomerase
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Target Validation |
T27325
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UniProt ID | |||||
EC Number |
EC 5.99.1.2
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Sequence |
MRVVRLLRLRAALTLLGEVPRRPASRGVPGSRRTQKGSGARWEKEKHEDGVKWRQLEHKG
PYFAPPYEPLPDGVRFFYEGRPVRLSVAAEEVATFYGRMLDHEYTTKEVFRKNFFNDWRK EMAVEEREVIKSLDKCDFTEIHRYFVDKAAARKVLSREEKQKLKEEAEKLQQEFGYCILD GHQEKIGNFKIEPPGLFRGRGDHPKMGMLKRRITPEDVVINCSRDSKIPEPPAGHQWKEV RSDNTVTWLAAWTESVQNSIKYIMLNPCSKLKGETAWQKFETARRLRGFVDEIRSQYRAD WKSREMKTRQRAVALYFIDKLALRAGNEKEDGEAADTVGCCSLRVEHVQLHPEADGCQHV VEFDFLGKDCIRYYNRVPVEKPVYKNLQLFMENKDPRDDLFDRLTTTSLNKHLQELMDGL TAKVFRTYNASITLQEQLRALTRAEDSIAAKILSYNRANRVVAILCNHQRATPSTFEKSM QNLQTKIQAKKEQVAEARAELRRARAEHKAQGDGKSRSVLEKKRRLLEKLQEQLAQLSVQ ATDKEENKQVALGTSKLNYLDPRISIAWCKRFRVPVEKIYSKTQRERFAWALAMAGEDFE F |
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Structure |
1A31; 1A35; 1A36; 1EJ9; 1K4S; 1K4T; 1LPQ; 1NH3; 1R49; 1RR8; 1RRJ; 1SC7; 1SEU; 1T8I; 1TL8
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Drugs and Mode of Action | |||||
Drug(s) | Belotecan hydrocholoride | Drug Info | Approved | Small-cell lung cancer | [551871] |
Irinotecan | Drug Info | Approved | Colorectal cancer | [535668], [541905] | |
Sphingosomal topotecan | Drug Info | Approved | Cancer | [529315] | |
Topetecan | Drug Info | Approved | Small-cell lung cancer | [538552] | |
Topotecan | Drug Info | Approved | Ovarian cancer | [536361], [542109] | |
9-Nitrocamptothecin (9-NC) | Drug Info | Phase 2 | Discovery agent | [521755] | |
CKD602 | Drug Info | Phase 2 | Cancer | [521961] | |
NK-611 | Drug Info | Discontinued in Phase 2 | Solid tumours | [545190] | |
Liposomal lurtotecan | Drug Info | Discontinued in Phase 1 | Lung cancer | [546810] | |
Datelliptium chloride | Drug Info | Terminated | Breast cancer | [544836] | |
Inhibitor | (5Z,9Z)-5,9-heptacosadienoic acid | Drug Info | [526463] | ||
10-hydroxycamptothecin | Drug Info | [538086] | |||
3,3'-(4-phenylpyridine-2,6-diyl)diphenol | Drug Info | [530854] | |||
3-(4-phenyl-2,4'-bipyridin-6-yl)phenol | Drug Info | [530854] | |||
3-(4-phenyl-6-(thiophen-2-yl)pyridin-2-yl)-phenol | Drug Info | [530854] | |||
3-(4-phenyl-6-(thiophen-3-yl)pyridin-2-yl)-phenol | Drug Info | [530854] | |||
3-(6-phenyl-2,4'-bipyridin-4-yl)phenol | Drug Info | [530854] | |||
4-(4,6-diphenylpyridin-2-yl)phenol | Drug Info | [530854] | |||
4-(6-phenyl-2,4'-bipyridin-4-yl)phenol | Drug Info | [530854] | |||
4-hydroxysaprothoquinone | Drug Info | [526391] | |||
CHO793076 | Drug Info | [529993] | |||
CKD602 | Drug Info | [538150] | |||
E-758 | Drug Info | [544051] | |||
Homocamptothecins (hCPTs) | Drug Info | [535629] | |||
Liposomal lurtotecan | Drug Info | [527009] | |||
Luteolin | Drug Info | [535459] | |||
NK-611 | Drug Info | [534608] | |||
NSC-341622 | Drug Info | [530411] | |||
ROSETTACIN | Drug Info | [530411] | |||
Topetecan | Drug Info | [550963] | |||
TOPOSTATIN | Drug Info | [526096] | |||
Activator | 2,3-Dimethoxybenzo[i]phenanthridines | Drug Info | [535678] | ||
Binder | 5-hydroxy-1H-indole-3-acetic acid | Drug Info | [538015] | ||
7-amino-4-hydroxy-2-naphthalenesulfonic acid | Drug Info | [538015] | |||
Dibenzo-p-dioxin-2-carboxylic acid | Drug Info | [538015] | |||
Quinizarin | Drug Info | [538015] | |||
Inducer | 9-Nitrocamptothecin (9-NC) | Drug Info | [535637] | ||
KT6006 | Drug Info | [535806] | |||
KT6528 | Drug Info | [535806] | |||
Modulator | Belotecan hydrocholoride | Drug Info | [529023], [530110] | ||
Datelliptium chloride | Drug Info | [531121] | |||
Irinotecan | Drug Info | [556264] | |||
Sphingosomal topotecan | Drug Info | [529315] | |||
Topotecan | Drug Info | [556264] | |||
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM) | |||||
TEP | EXP Info | ||||
Pathways | |||||
WikiPathways | Integrated Pancreatic Cancer Pathway | ||||
References | |||||
Ref 521755 | ClinicalTrials.gov (NCT00250068) Study of Aerosolized Liposomal 9-Nitro-20 (S)- Camptothecin (L9NC). U.S. National Institutes of Health. | ||||
Ref 521961 | ClinicalTrials.gov (NCT00430144) Belotecan (CKD-602) in Recurrent or Progressive Carcinoma of Uterine Cervix. U.S. National Institutes of Health. | ||||
Ref 535668 | New drugs for the treatment of cancer, 1990-2001. Isr Med Assoc J. 2002 Dec;4(12):1124-31. | ||||
Ref 536361 | Natural 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 538552 | FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 020671. | ||||
Ref 541905 | (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 542109 | (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 544836 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001278) | ||||
Ref 545190 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002418) | ||||
Ref 526096 | J Nat Prod. 2001 Feb;64(2):204-7.Isoaurostatin, a novel topoisomerase inhibitor produced by Thermomonospora alba. | ||||
Ref 526391 | J Nat Prod. 2002 Jul;65(7):1016-20.Bioactive abietane and seco-abietane diterpenoids from Salvia prionitis. | ||||
Ref 526463 | J 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 527009 | Phase 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 529023 | Belotecan, 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 529993 | Bioorg Med Chem Lett. 2009 Apr 1;19(7):2018-21. Epub 2009 Feb 12.Synthesis of new camptothecin analogs with improved antitumor activities. | ||||
Ref 530110 | Impact of natural products on developing new anti-cancer agents. Chem Rev. 2009 Jul;109(7):3012-43. | ||||
Ref 530411 | Bioorg 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 530854 | Bioorg 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 531121 | Toxicity 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 534608 | DNA topoisomerase II poisons and inhibitors. Cancer Chemother Biol Response Modif. 1997;17:114-31. | ||||
Ref 535459 | Luteolin, an emerging anti-cancer flavonoid, poisons eukaryotic DNA topoisomerase I. Biochem J. 2002 Sep 1;366(Pt 2):653-61. | ||||
Ref 535629 | Homocamptothecins: potent topoisomerase I inhibitors and promising anticancer drugs. Crit Rev Oncol Hematol. 2003 Jan;45(1):91-108. | ||||
Ref 535637 | A 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 535678 | 2,3-Dimethoxybenzo[i]phenanthridines: topoisomerase I-targeting anticancer agents. Bioorg Med Chem. 2003 Feb 20;11(4):521-8. | ||||
Ref 535806 | Induction of mammalian DNA topoisomerase I mediated DNA cleavage by antitumor indolocarbazole derivatives. Biochemistry. 1992 Dec 8;31(48):12069-75. | ||||
Ref 538015 | Comparison 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 538086 | Upregulation 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 538150 | Antitumor 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. |
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