Target Information

Target General Infomation
Target ID
T09826
Former ID
TTDNC00422
Target Name
Toposisomerase-1
Gene Name
TOP1
Synonyms
DNA topoisomerase 1; DNA topoisomerase I; TOP1
Target Type
Clinical Trial
Disease Acquired immune deficiency syndrome [ICD9: 42; ICD10: B20]
Advanced ovarian cancer; Lung cancer [ICD9:183, 162; ICD10: C56, C33-C34]
Acute lymphoblastic leukemia [ICD9: 204.0, 556; ICD10: C91.0]
Bladder cancer [ICD9: 188; ICD10: C67]
Breast cancer [ICD9: 174, 175; ICD10: C50]
Colorectal cancer [ICD9: 153, 154; ICD10: C18-C21]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Esophageal cancer [ICD9: 150; ICD10: C15]
Glioblastoma multiforme; Myelodysplastic syndrome [ICD9:191, 238.7; ICD10: C71, D46]
Gastric cancer [ICD9: 151; ICD10: C16]
Human immunodeficiency virus infection [ICD9: 279.3; ICD10: B20-B26]
Lymphoma [ICD9: 202.8, 208.9; ICD10: C81-C86]
Late-stage solid tumors [ICD9: 140-199, 210-229; ICD10: C00-C75, C7A, C7B, D10-D36, D3A]
Metastatic breast cancer; Metastatic colorectal cancer [ICD9:153, 154; ICD10: C50, C18-C21]
Metastatic breast cancer [ICD10: C50]
Ovarian cancer [ICD9: 183; ICD10: C56]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Unspecified [ICD code not available]
Function
Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription 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 ofa 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). Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells. .
BioChemical Class
DNA topoisomerase
UniProt ID
P11387
EC Number
EC 5.99.1.2
Sequence
MSGDHLHNDSQIEADFRLNDSHKHKDKHKDREHRHKEHKKEKDREKSKHSNSEHKDSEKK
HKEKEKTKHKDGSSEKHKDKHKDRDKEKRKEEKVRASGDAKIKKEKENGFSSPPQIKDEP
EDDGYFVPPKEDIKPLKRPRDEDDADYKPKKIKTEDTKKEKKRKLEEEEDGKLKKPKNKD
KDKKVPEPDNKKKKPKKEEEQKWKWWEEERYPEGIKWKFLEHKGPVFAPPYEPLPENVKF
YYDGKVMKLSPKAEEVATFFAKMLDHEYTTKEIFRKNFFKDWRKEMTNEEKNIITNLSKC
DFTQMSQYFKAQTEARKQMSKEEKLKIKEENEKLLKEYGFCIMDNHKERIANFKIEPPGL
FRGRGNHPKMGMLKRRIMPEDIIINCSKDAKVPSPPPGHKWKEVRHDNKVTWLVSWTENI
QGSIKYIMLNPSSRIKGEKDWQKYETARRLKKCVDKIRNQYREDWKSKEMKVRQRAVALY
FIDKLALRAGNEKEEGETADTVGCCSLRVEHINLHPELDGQEYVVEFDFLGKDSIRYYNK
VPVEKRVFKNLQLFMENKQPEDDLFDRLNTGILNKHLQDLMEGLTAKVFRTYNASITLQQ
QLKELTAPDENIPAKILSYNRANRAVAILCNHQRAPPKTFEKSMMNLQTKIDAKKEQLAD
ARRDLKSAKADAKVMKDAKTKKVVESKKKAVQRLEEQLMKLEVQATDREENKQIALGTSK
LNYLDPRITVAWCKKWGVPIEKIYNKTQREKFAWAIDMADEDYEF
Structure
1A31; 1A35; 1A36; 1EJ9; 1K4S; 1K4T; 1LPQ; 1NH3; 1R49; 1RR8; 1RRJ; 1SC7; 1SEU; 1T8I; 1TL8
Drugs and Mode of Action
Drug(s) Camptothecin Drug Info Phase 3 Solid tumours [1]
Edotecarin Drug Info Phase 3 Gastric cancer [2]
Etirinotecan pegol Drug Info Phase 3 Metastatic breast cancer [3]
Exatecan Drug Info Phase 3 Solid tumours [4]
Karenitecin Drug Info Phase 3 Advanced ovarian cancer; Lung cancer [5]
Rubitecan Drug Info Phase 3 Human immunodeficiency virus infection [6]
9-AMINOCAMPTOTHECIN Drug Info Phase 2 Acquired immune deficiency syndrome [7]
Anthracycline Drug Info Phase 2 Solid tumours [8]
AR-67 Drug Info Phase 2 Glioblastoma multiforme; Myelodysplastic syndrome [9]
Beta-Lapachone Drug Info Phase 2 Solid tumours [10]
CRLX101 Drug Info Phase 2 Late-stage solid tumors [11]
DIFLOMOTECAN Drug Info Phase 2 Solid tumours [12]
EQ-917 Drug Info Phase 2 Cancer [13]
Gimatecan Drug Info Phase 2 Breast cancer [14]
LE-SN38 Drug Info Phase 2 Colorectal cancer [15]
PEG-SN38 Drug Info Phase 2 Metastatic breast cancer; Metastatic colorectal cancer [16], [15]
Pegamotecan Drug Info Phase 2 Esophageal cancer [17]
Polyglutamate camptothecin Drug Info Phase 2 Solid tumours [18]
SN-38 Drug Info Phase 2 Cancer [15], [19]
TLC-388 Drug Info Phase 2 Solid tumours [20]
XR-5000 Drug Info Phase 2 Colorectal cancer [21]
ABI-011 Drug Info Phase 1 Solid tumours [22]
Afeletecan Drug Info Phase 1 Breast cancer [23]
CZ-48 Drug Info Phase 1 Cancer [24]
Daniquidone Drug Info Phase 1 Lymphoma [25]
DRF-1042 Drug Info Phase 1 Solid tumours [26]
ELOMOTECAN HYDROCHLORIDE Drug Info Phase 1 Solid tumours [27]
Genz-644282 Drug Info Phase 1 Solid tumours [28]
GZ402674 Drug Info Phase 1 Solid tumours [29]
INTOPLICINE Drug Info Phase 1 Solid tumours [30]
MLN-576 Drug Info Phase 1 Acute lymphoblastic leukemia [31]
Namitecan Drug Info Phase 1 Solid tumours [32]
Tafluposide Drug Info Phase 1 Cancer [33]
XMT-1001 Drug Info Phase 1 Solid tumours [34]
(S)-DRF-1042 Drug Info Clinical trial Bladder cancer [35]
BECATECARIN Drug Info Discontinued in Phase 3 Solid tumours [36]
Atiratecan Drug Info Discontinued in Phase 2 Colorectal cancer [37]
Lurtotecan Drug Info Discontinued in Phase 2 Ovarian cancer [38]
S-16020-2 Drug Info Discontinued in Phase 2 Solid tumours [39]
DE-310 Drug Info Discontinued in Phase 1 Cancer [40]
BE-13793C Drug Info Terminated Cancer [41]
BN-80245 Drug Info Terminated Cancer [42]
CZ-112 Drug Info Terminated Solid tumours [43]
ED-110 Drug Info Terminated Cancer [44]
PIROXANTRONE Drug Info Terminated Cancer [45]
TAN-1496 Drug Info Terminated Cancer [46]
Inhibitor (S)-DRF-1042 Drug Info [47]
9-AMINOCAMPTOTHECIN Drug Info [48]
A35566-A Drug Info [47]
Afeletecan Drug Info [49]
AR-67 Drug Info [50]
ATI-1150 Drug Info [47]
Atiratecan Drug Info [51]
BN-80245 Drug Info [52]
CZ-112 Drug Info [53]
CZ-48 Drug Info [53]
DE-310 Drug Info [54]
DIFLOMOTECAN Drug Info [55]
DRF-1042 Drug Info [48], [56]
DTS-108 Drug Info [47]
Edotecarin Drug Info [2]
EQ-917 Drug Info [57]
Etirinotecan pegol Drug Info [58]
Exatecan Drug Info [59]
Genz-644282 Drug Info [60]
Gimatecan Drug Info [61]
IDN-5174 Drug Info [47]
IDN-6384 Drug Info [47]
Karenitecin Drug Info [62]
LE-SN38 Drug Info [63]
Lurtotecan Drug Info [47]
MEN-14295 Drug Info [47]
Namitecan Drug Info [64]
PEG-SN38 Drug Info [65]
Pegamotecan Drug Info [66]
Polyglutamate camptothecin Drug Info [1]
Rubitecan Drug Info [67]
TLC-388 Drug Info [20]
XMT-1001 Drug Info [68]
Modulator ABI-011 Drug Info
Anthracycline Drug Info
BE-13793C Drug Info
BECATECARIN Drug Info [69]
Beta-Lapachone Drug Info [10]
Camptothecin Drug Info [1]
CRISNATOL MESILATE Drug Info [70]
CRLX101 Drug Info
Daniquidone Drug Info
ED-110 Drug Info [71]
ELOMOTECAN HYDROCHLORIDE Drug Info
GZ402674 Drug Info [47]
INTOPLICINE Drug Info
MLN-576 Drug Info [31]
PIROXANTRONE Drug Info
S-16020-2 Drug Info
SN-38 Drug Info
Tafluposide Drug Info [72]
TAN-1496 Drug Info [73]
TH-1320 Drug Info [47]
XR-5000 Drug Info [21]
Stimulator SER-203 Drug Info [47]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
DRM DRM Info
Pathways
NetPath Pathway IL2 Signaling Pathway
PANTHER Pathway DNA replication
Pathway Interaction Database Caspase Cascade in Apoptosis
WikiPathways Integrated Pancreatic Cancer Pathway
References
REF 1Topoisomerase I inhibitors: camptothecins and beyond. Nat Rev Cancer. 2006 Oct;6(10):789-802.
REF 2Edotecarin: a novel topoisomerase I inhibitor. Clin Colorectal Cancer. 2005 May;5(1):27-36.
REF 3ClinicalTrials.gov (NCT01492101) The BEACON Study (Breast Cancer Outcomes With NKTR-102). U.S. National Institutes of Health.
REF 4ClinicalTrials.gov (NCT00023972) Gemcitabine With or Without Exatecan Mesylate in Treating Patients With Locally Advanced or Metastatic Pancreatic Cancer. U.S. National Institutes of Health.
REF 5ClinicalTrials.gov (NCT00477282) Karenitecin Versus Topotecan in Patients With Advanced Epithelial Ovarian Cancer. U.S. National Institutes of Health.
REF 6ClinicalTrials.gov (NCT00005869) Nitrocamptothecin Compared With Gemcitabine in Treating Patients With Unresectable Locally Advanced or Metastatic Pancreatic Cancer. U.S. National Institutes of Health.
REF 7ClinicalTrials.gov (NCT00001427) A Phase II Trial of 72-Hour Continuous IV Infusion of 9-Aminocamptothecin With G-CSF Support in Patients With Advanced Ovarian Cancer Previously Treated With Paclitaxel and Cisplatin. U.S. National Institutes of Health.
REF 8Multicentre, phase II study evaluating capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer. Eur J Cancer. 2004 Mar;40(4):536-42.
REF 9ClinicalTrials.gov (NCT01124539) Study of AR-67 in Adult Patients With Recurrence of Glioblastoma Multiforme (GBM) or Gliosarcoma. U.S. National Institutes of Health.
REF 10Cancer therapy with beta-lapachone. Curr Cancer Drug Targets. 2002 Sep;2(3):227-42.
REF 11ClinicalTrials.gov (NCT01803269) Topotecan Hydrochloride or Cyclodextrin-Based Polymer-Camptothecin CRLX101 in Treating Patients With Recurrent Small Cell Lung Cancer. U.S. National Institutes of Health.
REF 12ClinicalTrials.gov (NCT00080015) Diflomotecan (BN80915) Administered Once Every 3 Weeks in Treating Patients With Sensitive Small Cell Lung Cancer (SCLC). U.S. National Institutes of Health.
REF 13Phase II study of camtobell inj. (belotecan) in combination with cisplatin in patients with previously untreated, extensive stage small cell lung cancer. Lung Cancer. 2013 Jun;80(3):313-8.
REF 14A phase II trial of oral gimatecan for recurrent glioblastoma. J Neurooncol. 2013 Feb;111(3):347-53.
REF 15Randomized phase 2 study of pegylated SN-38 (EZN-2208) or irinotecan plus cetuximab in patients with advanced colorectal cancer. Cancer. 2013 Dec 15;119(24):4223-30.
REF 16ClinicalTrials.gov (NCT01036113) A Phase 2 Study of EZN-2208 in Patients With Metastatic Breast Cancer. U.S. National Institutes of Health.
REF 17ClinicalTrials.gov (NCT00080002) Efficacy of Pegamotecan (PEG-Camptothecin) in Localized or Metastatic Cancer of the Stomach or Gastroesophageal Junction. U.S. National Institutes of Health.
REF 18ClinicalTrials.gov (NCT00291837) CT-2106 for the Second Line Treatment of Ovarian Cancer. U.S. National Institutes of Health.
REF 19(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: 6925).
REF 20Topotecan - A novel topoisomerase I inhibitor: pharmacology and clinical experience. Oncology. 1999;56(1):1-12.
REF 21Phase II study of XR5000 (DACA) administered as a 120-h infusion in patients with recurrent glioblastoma multiforme. Ann Oncol. 2002 May;13(5):777-80.
REF 22ClinicalTrials.gov (NCT01163071) A Phase 1 Trial of ABI-011 in Patients With Advanced Solid Tumors or Lymphomas. U.S. National Institutes of Health.
REF 23Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800013469)
REF 24ClinicalTrials.gov (NCT00947739) Phase I and Pharmacology Study of Camptothecin-20-O-Propionate Hydrate (CZ48) in Patients With Solid Tumors or Lymphoma. U.S. National Institutes of Health.
REF 25ClinicalTrials.gov (NCT00450502) Safety of Batracylin in Patients With Solid Tumors and Lymphomas. U.S. National Institutes of Health.
REF 26Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014200)
REF 27ClinicalTrials.gov (NCT01435096) BN80927 in Patients With Advanced Malignant Solid Tumors. U.S. National Institutes of Health.
REF 28ClinicalTrials.gov (NCT00942799) Dose Escalation Study to Assess the Safety and Tolerability of Genz-644282 in Patients With Solid Tumors. U.S. National Institutes of Health.
REF 29Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800037203)
REF 30ClinicalTrials.gov (NCT00003713) Chemotherapy in Treating Patients With Advanced or Metastatic Solid Tumors. U.S. National Institutes of Health.
REF 31In vitro and in vivo characterization of XR11576, a novel, orally active, dual inhibitor of topoisomerase I and II. Anticancer Drugs. 2002 Jan;13(1):15-28.
REF 32ClinicalTrials.gov (NCT01748019) ST1968 Intravenous (Weekly) in Solid Tumors. U.S. National Institutes of Health.
REF 33Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800012192)
REF 34ClinicalTrials.gov (NCT00455052) A Study of Intravenous XMT-1001 in Patients With Advanced Solid Tumors. U.S. National Institutes of Health.
REF 35(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: 8261).
REF 36Clinical pipeline report, company report or official report of Exelixis.
REF 37Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800024385)
REF 38Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800004939)
REF 39Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800004159)
REF 40Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014192)
REF 41Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800005130)
REF 42Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800011416)
REF 43Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800011353)
REF 44Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002530)
REF 45Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800004116)
REF 46Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800004359)
REF 47(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: 2636).
REF 48Intraperitoneal topoisomerase-I inhibitors. Preliminary findings with 9-aminocamptothecin. Ann N Y Acad Sci. 2000;922:178-87.
REF 49The fate of camptothecin glycoconjugate: report of a clinical hold during a phase II study of BAY 56-3722 (formerly BAY 38-3441), in patients with recurrent or metastatic colorectal cancer resistant/refractory to irinotecan. Invest New Drugs. 2012 June; 30(3): 1208-1210.
REF 50Protracted dosing of the lipophilic camptothecin analogue AR-67 in non-small cell lung cancer xenografts and humans. Cancer Chemother Pharmacol. 2014 Jul;74(1):45-54.
REF 51Method development and validation of the simultaneous determination of a novel topoisomerase 1 inhibitor, the prodrug, and the active metabolite in human plasma using column-switching LC-MS/MS, and its application in a clinical trial. J Chromatogr B Analyt Technol Biomed Life Sci. 2011 Nov 15;879(30):3415-22.
REF 52BN 80245: An E-ring modified camptothecin with potent antiproliferative and topoisomerase I inhibitory activities. Bioorganic & Medicinal Chemistry Letters Volume 7, Issue 17, 9 September 1997, Pages2235-2238.
REF 53Pharmacology of camptothecin esters. Ann N Y Acad Sci. 2000;922:216-23.
REF 54DE-310, a macromolecular prodrug of the topoisomerase-I-inhibitor exatecan (DX-8951), in patients with operable solid tumors. Invest New Drugs. 2005 Aug;23(4):339-47.
REF 55Diflomotecan, a promising homocamptothecin for cancer therapy. Expert Opin Investig Drugs. 2009 Jan;18(1):69-75.
REF 56Safety, tolerability, and pharmacokinetics of a capsule formulation of DRF-1042, a novel camptothecin analog, in refractory cancer patients in a bridging phase I study. J Clin Pharmacol. 2005 Apr;45(4):453-60.
REF 57The efficacy and toxicity of belotecan (CKD-602), a camptothericin analogue topoisomerase I inhibitor, in patients with recurrent or refractory epithelial ovarian cancer. J Chemother. 2010 Jun;22(3):197-200.
REF 58Nonclinical pharmacokinetics and activity of etirinotecan pegol (NKTR-102), a long-acting topoisomerase 1 inhibitor, in multiple cancer models. Cancer Chemother Pharmacol. 2014 Dec;74(6):1125-37.
REF 59Phase I study of topoisomerase I inhibitor exatecan mesylate (DX-8951f) given as weekly 24-hour infusions three of every four weeks. Clin Cancer Res. 2001 Dec;7(12):3963-70.
REF 60Genz-644282, a novel non-camptothecin topoisomerase I inhibitor for cancer treatment. Clin Cancer Res. 2011 May 1;17(9):2777-87.
REF 61Gimatecan and other camptothecin derivatives poison Leishmania DNA-topoisomerase IB leading to a strong leishmanicidal effect. Biochem Pharmacol. 2013 May 15;85(10):1433-40.
REF 62Characterization of protein kinase chk1 essential for the cell cycle checkpoint after exposure of human head and neck carcinoma A253 cells to a novel topoisomerase I inhibitor BNP1350. Mol Pharmacol.2000 Mar;57(3):453-9.
REF 63Analysis of type of cell death induced by topoisomerase inhibitor SN-38 in human oral squamous cell carcinoma cell lines. Anticancer Res. 2012 Nov;32(11):4823-32.
REF 64Namitecan: a hydrophilic camptothecin with a promising preclinical profile. Curr Med Chem. 2012;19(21):3488-501.
REF 65EZN-2208 (PEG-SN38) overcomes ABCG2-mediated topotecan resistance in BRCA1-deficient mouse mammary tumors. PLoS One. 2012;7(9):e45248.
REF 66A phase II study of pegylated-camptothecin (pegamotecan) in the treatment of locally advanced and metastatic gastric and gastro-oesophageal junction adenocarcinoma. Cancer Chemother Pharmacol. 2009 Jan;63(2):363-70.
REF 67Rubitecan. Expert Opin Investig Drugs. 2006 Jan;15(1):71-9.
REF 68Pharmacokinetics and antitumor efficacy of XMT-1001, a novel, polymeric topoisomerase I inhibitor, in mice bearing HT-29 human colon carcinoma xenografts. Clin Cancer Res. 2012 May 1;18(9):2591-602.
REF 69Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
REF 70The ChEMBL database in 2017.
REF 71Indolocarbazole poisons of human topoisomerase I: regioisomeric analogues of ED-110. Bioorg Med Chem Lett. 1999 Jan 18;9(2):145-50.
REF 72Ex vivo effects of the dual topoisomerase inhibitor tafluposide (F 11782) on cells isolated from fresh tumor samples taken from patients with cancer. Anticancer Drugs. 2003 Jul;14(6):467-73.
REF 73TAN-1496 A, C and E, diketopiperazine antibiotics with inhibitory activity against mammalian DNA topoisomerase I. J Antibiot (Tokyo). 1994 Nov;47(11):1202-18.

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