Therapeutic Targets Database
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TTD Target ID: TTDS00080

Target Information
NameDNA topoisomerase II    
Type of targetSuccessful target    
SynonymsDNA gyrase    
Topo II    
Topoisomerase II    
Type II topoisomerase enzyme    
DiseaseAcute promyelocytic leukemia
[ICD9: 205.0   ICD10: C92.4]
[1]
Bacterial infections
[ICD9: 001-009, 010-018, 020-027, 030-041, 080-088, 090-099, 100-104   ICD10: A00-A09, A15-A19, A20-A28, A30-A49, A65-A69, A70-A74, A75-A79]
[2][3]
Cancer, unspecific
[ICD9: 140-229   ICD10: C00-C96]
[4][5][6]
Fungal diseases
[ICD9: 110-118   ICD10: B35-B49]
[7]
Herpes virus infection
[ICD9: 001-139, 042-075   ICD10: A00-B99, A80-A99, B00-B34]
[8]
Leishmania infections
[ICD9: 001-139, 296.0, 296.4, 296.6   ICD10: A00-B99, F30]
[9]
Malaria
[ICD9: 084   ICD10: B50-B54]
[10]
Trichomoniasis
[ICD9: 131   ICD10: A59]
[11]
Drug(s)AclarubicinApprovedCancer[12][8]
AmsacrineApprovedAcute lymphoblastic leukemia[13]
BesifloxacinApprovedBacterial conjunctivitis
CinoxacinApprovedUrinary tract infections[14]
CiprofloxacinApprovedBacterial infections[15]
DexrazoxaneApprovedBreast Cancer[12][16]
Dhaq diacetateApprovedCancer[17][6]
DoxorubicinApprovedCancers[18][19]
EnoxacinApprovedBacterial infections[20]
EpirubicinApprovedCancers[21]
EtoposideApprovedCancers[8][10][13]
FleroxacinApprovedBacterial infections[22]
FluoroquinoloneApprovedBacterial infections[23]
GatifloxacinApprovedRespiratory tract infections[24]
GatifloxacinApprovedRespiratory tract infections[24]
GemifloxacinApprovedBacterial infections[25]
IdarubicinApprovedAcute myeloid leukemia[26]
LevofloxacinApprovedBacterial infections[27]
LomefloxacinApprovedBacterial infections[28]
LucanthoneApprovedCancer[29]
MitoxantroneApprovedCancers[30]
MoxifloxacinApprovedBacterial infections[31]
Nalidixic AcidApprovedBacterial infections[15]
NorfloxacinApprovedBacterial infections[10][15]
NovobiocinApprovedBacterial infections[32]
NovobiocineApprovedBacterial infections[23]
OfloxacinApprovedBacterial infections[15]
PefloxacinApprovedGonococcal urethritis in males[20]
QuinolonesApprovedTuberculosis[33]
RosoxacinApprovedBacterial infections[34]
SparfloxacinApprovedBacterial infections[27]
TeniposideApprovedAcute lymphocytic leukemia[35]
TrovafloxacinApprovedBacterial infections[36]
ValrubicinApprovedBladder cancer[37]
ciprofloxacinApprovedBacterial infections[38]
SNS-595Phase IIOvarian cancer[39]
AEZS-112Phase I completedLymphoma
2140944Phase IBacterial infections
GSK945237Phase IBacterial infections[40]
Iboctadekin + DoxilPhase IOvarian cancer[40]
TOP-53Phase ILung tumors and lung metastatic tumors[41]
GarenoxacinDiscontinuedEndocarditis[42]
SalvicinePreclinicalCancers[43]
BioChemical ClassIsomerases    
EC NumberEC 5.99.1.3
UniProt IDP0AES4
P0AES6
P11388
Q02880
PDB Structure3QX3.    
SequenceMEVSPLQPVNENMQVNKIKKNEDAKKRLSVERIYQKKTQLEHILLRPDTYIGSVELVTQQ MWVYDEDVGINYREVTFVPGLYKIFDEILVNAADNKQRDPKMSCIRVTIDPENNLISIWN NGKGIPVVEHKVEKMYVPALIFGQLLTSSNYDDDEKKVTGGRNGYGAKLCNIFSTKFTVE TASREYKKMFKQTWMDNMGRAGEMELKPFNGEDYTCITFQPDLSKFKMQSLDKDIVALMV RRAYDIAGSTKDVKVFLNGNKLPVKGFRSYVDMYLKDKLDETGNSLKVIHEQVNHRWEVC LTMSEKGFQQISFVNSIATSKGGRHVDYVADQIVTKLVDVVKKKNKGGVAVKAHQVKNHM WIFVNALIENPTFDSQTKENMTLQPKSFGSTCQLSEKFIKAAIGCGIVESILNWVKFKAQ VQLNKKCSAVKHNRIKGIPKLDDANDAGGRNSTECTLILTEGDSAKTLAVSGLGVVGRDK YGVFPLRGKILNVREASHKQIMENAEINNIIKIVGLQYKKNYEDEDSLKTLRYGKIMIMT DQDQDGSHIKGLLINFIHHNWPSLLRHRFLEEFITPIVKVSKNKQEMAFYSLPEFEEWKS STPNHKKWKVKYYKGLGTSTSKEAKEYFADMKRHRIQFKYSGPEDDAAISLAFSKKQIDD RKEWLTNFMEDRRQRKLLGLPEDYLYGQTTTYLTYNDFINKELILFSNSDNERSIPSMVD GLKPGQRKVLFTCFKRNDKREVKVAQLAGSVAEMSSYHHGEMSLMMTIINLAQNFVGSNN LNLLQPIGQFGTRLHGGKDSASPRYIFTMLSSLARLLFPPKDDHTLKFLYDDNQRVEPEW YIPIIPMVLINGAEGIGTGWSCKIPNFDVREIVNNIRRLMDGEEPLPMLPSYKNFKGTIE ELAPNQYVISGEVAILNSTTIEISELPVRTWTQTYKEQVLEPMLNGTEKTPPLITDYREY HTDTTVKFVVKMTEEKLAEAERVGLHKVFKLQTSLTCNSMVLFDHVGCLKKYDTVLDILR DFFELRLKYYGLRKEWLLGMLGAESAKLNNQARFILEKIDGKIIIENKPKKELIKVLIQR GYDSDPVKAWKEAQQKVPDEEENEESDNEKETEKSDSVTDSGPTFNYLLDMPLWYLTKEK KDELCRLRNEKEQELDTLKRKSPSDLWKEDLATFIEELEAVEAKEKQDEQVGLPGKGGKA KGKKTQMAEVLPSPRGQRVIPRITIEMKAEAEKKNKKKIKNENTEGSPQEDGVELEGLKQ RLEKKQKREPGTKTKKQTTLAFKPIKKGKKRNPWSDSESDRSSDESNFDVPPRETEPRRA ATKTKFTMDLDSDEDFSDFDEKTDDEDFVPSDASPPKTKTSPKLSNKELKPQKSVVSDLE ADDVKGSVPLSSSPPATHFPDETEITNPVPKKNVTVKKTAAKSQSSTSTTGAKKRAAPKG TKRDPALNSGVSQKPDPAKTKNRRKRKPSTSDDSDSNFEKIVSKAVTSKKSKGESDDFHM DFDSAVAPRAKSVRAKKPIKYLEESDEDDLF
Related US Patent6,420,377
6,441,198
6,465,008
6,608,087
6,632,809
Target ValidationClick to Find Target Validation Information.    
QSAR ModelClick to Find Target QSAR Model.    
Inhibitor1,3,7-trihydroxyacridone[8]
1-Methoxy-3- (oxiran-2-ylmethoxy)-9H-xanthen-9-one[44]
2- (2-Aminoethyl)anthra[1,9-cd]pyrazol-6[45]
2- (2-Hydroxyethyl)anthra[1,9-cd]pyrazol-6[45]
3,3'- (4-phenylpyridine-2,6-diyl)diphenol[46]
3- (2,6-diphenylpyridin-4-yl)phenol[46]
3- (2-phenyl-6-[46]
3- (2-phenyl-6-[46]
3- (4-phenyl-6-[46]
3- (4-phenyl-6-[46]
3- (6-[46]
4'-Demethyl-4beta-amino-4-desoxypodophyllotoxin[47]
4'-Demethyl-epipodophyllotoxin[47]
4,4'- (4-phenylpyridine-2,6-diyl)diphenol[46]
4- (furan-3-yl)-2,6-di[48]
7-chloro-1,3-dihydroxyacridone[8]
A-62176[49]
Aclarubicin[12][8]
Amifloxacin[15]
Amsacrine[13]
Anthracycline[35]
Cinoxacin[14]
Ciprofloxacin[15]
Clorobiocin[50]
Coumermycin A1[15]
DEMETHYLZEYLASTERONE[51]
Dexrazoxane[12][16]
Dhaq diacetate[17][6]
Doxorubicin[18][19]
ER-37328[52]
Ellipticine[11]
Enoxacin[20]
Epirubicin[21]
Etoposide[8][10][13]
Fleroxacin[22]
Fluoroquinolone[23]
Fluoroquinolones[11]
GSK945237[40]
Garenoxacin[42]
Gatifloxacin[24]
Gatifloxacin[24]
Gemifloxacin[25]
Genistein[53]
Howiinol A (GHM-10)[54]
ICRF-154[1]
ICRF-193[1]
Iboctadekin + Doxil[40]
Idarubicin[26]
LOSOXANTRONE[55]
LUPEOL[56]
Levofloxacin[27]
Lomefloxacin[28]
Lucanthone[29]
Mitoxantrone[30]
Moxifloxacin[31]
Nalidixic Acid[15]
Norfloxacin[10][15]
Novobiocin[32]
Ofloxacin[15]
Olean-12-en-3beta,15alpha-diol[56]
Oxolinic acid[15]
PIROXANTRONE[55]
Pefloxacin[20]
Phosphoaminophosphonic Acid-Adenylate Ester[57]
Podophyllotoxin[58]
Pumiliotoxin 251D[59]
Quinolones[33]
Ro-23-9424[59]
Rosoxacin[34]
SNS-595[39]
Salvicine[43]
Sparfloxacin[27]
TOP-53[41]
TOPOSTATIN[60]
Teniposide[35]
Trovafloxacin[36]
Valrubicin[37]
ciprofloxacin[38]
makaluvamine N[61]
BinderCBR-2092[59]
Ciprofloxacin+dexamethasone[62]
Novobiocine[23]
Ofloxacin otic[62]
Ro-23-9424[59]
Toll-like receptor 4 inhibition[59]
MultitargetCiprofloxacin[15]
Gatifloxacin[24]
Gemifloxacin[25]
Iboctadekin + Doxil[40]
Levofloxacin[27]
Moxifloxacin[31]
Sparfloxacin[27]
Cross References 3D Structure
Related Literature
On-Line Medical Dictionary
Ref 1The catalytic DNA topoisomerase II inhibitor ICRF-193 and all-trans retinoic acid cooperatively induce granulocytic differentiation of acute promyelocytic leukemia cells: candidate drugs for chemo-differentiation therapy against acute promyelocytic leukemia. Exp Hematol. 2002 Nov;30(11):1273-82. To Reference
Ref 2Activity of and resistance to moxifloxacin in Staphylococcus aureus. Antimicrob Agents Chemother. 2003 Apr;47(4):1410-5. To Reference
Ref 3Inhibitory activity of NM394, the active form of prodrug prulifloxacin against type II topoisomerase from Pseudomonas aeruginosa. Jpn J Antibiot. 2002 Dec;55(6):882-5. To Reference
Ref 4Phenoxodiol (2H-1-benzopyran-7-0,1,3-(4-hydroxyphenyl)), a novel isoflavone derivative, inhibits DNA topoisomerase II by stabilizing the cleavable complex. Anticancer Res. 2002 Sep-Oct;22(5):2581-5. To Reference
Ref 5Molecular cloning and identification of a point mutation in the topoisomerase II cDNA from an etoposide-resistant Chinese hamster ovary cell line. J Biol Chem. 1993 Jan 25;268(3):2160-5. To Reference
Ref 6Topoisomerase II is required for mitoxantrone to signal nuclear factor kappa B activation in HL60 cells. J Biol Chem. 2000 Aug 18;275(33):25231-8. To Reference
Ref 7Molecular cloning and expression of the Candida albicans TOP2 gene allows study of fungal DNA topoisomerase II inhibitors in yeast. Biochem J. 1997 May 15;324 ( Pt 1):329-39. To Reference
Ref 81,3-Dihydroxyacridone derivatives as inhibitors of herpes virus replication. Antiviral Res. 2000 Feb;45(2):123-34. To Reference
Ref 9Cloning, functional analysis and post-transcriptional regulation of a type II DNA topoisomerase from Leishmania infantum. A new potential target for anti-parasite drugs. Nucleic Acids Res. 2003 Aug 15;31(16):4917-28. To Reference
Ref 10Gametocytocidal activity of pyronaridine and DNA topoisomerase II inhibitors against multidrug-resistant Plasmodium falciparum in vitro. Parasitol Int. 2000 Feb;48(4):275-80. To Reference
Ref 11In vitro sensitivity of Trichomonas vaginalis to DNA topoisomerase II inhibitors. Southeast Asian J Trop Med Public Health. 2000 Mar;31(1):118-22. To Reference
Ref 12Linker length in podophyllotoxin-acridine conjugates determines potency in vivo and in vitro as well as specificity against MDR cell lines. Anticancer Drug Des. 2001 Dec;16(6):305-15. To Reference
Ref 13Design of two etoposide-amsacrine conjugates: topoisomerase II and tubuline polymerization inhibition and relation to cytotoxicity. Anticancer Drug Des. 2000 Dec;15(6):413-21. To Reference
Ref 14The interaction and transport of beta-lactam antibiotics with the cloned rat renal organic anion transporter 1. J Pharmacol Exp Ther. 1999 Aug;290(2):672-7. To Reference
Ref 15Activity of fluoroquinolone antibiotics against Plasmodium falciparum in vitro. Antimicrob Agents Chemother. 1988 Aug;32(8):1182-6. To Reference
Ref 16Improved targeting of brain tumors using dexrazoxane rescue of topoisomerase II combined with supralethal doses of etoposide and teniposide. Clin Cancer Res. 1998 Jun;4(6):1367-73. To Reference
Ref 17The hypoxia-activated ProDrug AQ4N penetrates deeply in tumor tissues and complements the limited distribution of mitoxantrone. Cancer Res. 2009 Feb 1;69(3):940-7. Epub 2009 Jan 27. To Reference
Ref 18NK314, a topoisomerase II inhibitor that specifically targets the alpha isoform. J Biol Chem. 2008 Aug 29;283(35):23711-20. Epub 2008 Jul 2. To Reference
Ref 19Proteasome inhibition circumvents solid tumor resistance to topoisomerase II-directed drugs. Cancer Res. 2000 May 1;60(9):2429-34. To Reference
Ref 20Clinical pharmacokinetics of the newer antibacterial 4-quinolones. Clin Pharmacokinet. 1988 Feb;14(2):96-121. To Reference
Ref 21Topoisomerase II alpha and responsiveness of breast cancer to adjuvant chemotherapy. J Natl Cancer Inst. 2009 May 6;101(9):644-50. Epub 2009 Apr 28. To Reference
Ref 22Fleroxacin overview. Chemotherapy. 1996 Mar;42 Suppl 1:1-9. To Reference
Ref 23Has nature already identified all useful antibacterial targets? Curr Opin Microbiol. 2008 Oct;11(5):387-92. Epub 2008 Oct 6. To Reference
Ref 24Antimicrob Agents Chemother. 1998 Oct;42(10):2678-81.Inhibitory activities of gatifloxacin (AM-1155), a newly developed fluoroquinolone, against bacterial and mammalian type II topoisomerases. To Reference
Ref 25Gemifloxacin for the treatment of respiratory tract infections: in vitro susceptibility, pharmacokinetics and pharmacodynamics, clinical efficacy, and safety. Pharmacotherapy. 2005 May;25(5):717-40. To Reference
Ref 26Formation and longevity of idarubicin-induced DNA topoisomerase II cleavable complexes in K562 human leukaemia cells. Biochem Pharmacol. 2002 May 15;63(10):1807-15. To Reference
Ref 27DNA gyrase, topoisomerase IV, and the 4-quinolones. Microbiol Mol Biol Rev. 1997 Sep;61(3):377-92. To Reference
Ref 28Inhibition of human topoisomerase IIalpha by fluoroquinolones and ultraviolet A irradiation. Toxicol Sci. 2002 Sep;69(1):16-22. To Reference
Ref 29Clonogenicity of human leukemic cells protected from cell-lethal agents by heat shock protein 70. Cell Stress Chaperones. 2005 Spring;10(1):37-45. To Reference
Ref 30Acute promyelocytic leukemic involvement of the optic nerves following mitoxantrone treatment for multiple sclerosis. J Neurol Sci. 2008 Oct 15;273(1-2):144-7. Epub 2008 Aug 6. To Reference
Ref 31Quinolones as enhancers of camptothecin-induced cytotoxic and anti-topoisomerase I effects. Biochem Pharmacol. 2008 Mar 15;75(6):1272-81. Epub 2007 Dec 3. To Reference
Ref 32Transcriptional responses of Bacillus subtillis and thuringiensis to antibiotics and anti-tumour drugs. Int J Mol Med. 2009 Jan;23(1):33-9. To Reference
Ref 33Annu Rev Pharmacol Toxicol. 2005;45:529-64.The magic bullets and tuberculosis drug targets. To Reference
Ref 34Inhibition of Micrococcus luteus DNA gyrase by norfloxacin and 10 other quinolone carboxylic acids. Antimicrob Agents Chemother. 1986 Apr;29(4):598-601. To Reference
Ref 35Topoisomerases: therapeutic value. Ann Pharm Fr. 1996;54(1):40-4. To Reference
Ref 36Topoisomerase II inhibition involves characteristic chromosomal expression patterns. BMC Genomics. 2008 Jul 8;9:324. To Reference
Ref 37Metabolic activation of N-acylanthracyclines precedes their interaction with DNA topoisomerase II. NCI Monogr. 1987;(4):111-5. To Reference
Ref 38Isobolographic analysis of pharmacodynamic interactions between antifungal agents and ciprofloxacin against Candida albicans and Aspergillus fumigatus. Antimicrob Agents Chemother. 2008 Jun;52(6):2196-204. Epub 2008 Feb 25. To Reference
Ref 39Emerging drugs for ovarian cancer. Expert Opin Emerg Drugs. 2008 Sep;13(3):523-36. To Reference
Ref 40GSK. Product Development Pipeline. February 2009. To Reference
Ref 41DNA topoisomerase II as the target for the anticancer drug TOP-53: mechanistic basis for drug action. Biochemistry. 2001 Jan 23;40(3):712-8. To Reference
Ref 42The inhibition and selectivity of bacterial topoisomerases by BMS-284756 and its analogues. J Antimicrob Chemother. 2001 Aug;48(2):195-201. To Reference
Ref 43Salvicine, a novel topoisomerase II inhibitor, exerts its potent anticancer activity by ROS generation. Acta Pharmacol Sin. 2007 Sep;28(9):1460-5. To Reference
Ref 44Eur J Med Chem. 2010 Sep;45(9):4221-8. Epub 2010 Jun 17.Synthesis and pharmacological evaluation of new methyloxiranylmethoxyxanthone analogues. To Reference
Ref 45Bioorg Med Chem. 2010 Jun 1;18(11):3974-84. Epub 2010 Apr 18.Design, synthesis and biological evaluation of a novel series of anthrapyrazoles linked with netropsin-like oligopyrrole carboxamides as anticancer agents. To Reference
Ref 46Bioorg 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 47J. Nat. Prod. 52(3):606-613 (1989) To Reference
Ref 48Bioorg Med Chem Lett. 2010 Jan 1;20(1):42-7. Epub 2009 Nov 14.2,6-Dithienyl-4-furyl pyridines: Synthesis, topoisomerase I and II inhibition, cytotoxicity, structure-activity relationship, and docking study. To Reference
Ref 49J Med Chem. 1998 Oct 22;41(22):4273-8.Design of new topoisomerase II inhibitors based upon a quinobenzoxazine self-assembly model. To Reference
Ref 50Tsai FT, Singh OM, Skarzynski T, Wonacott AJ, Weston S, Tucker A, Pauptit RA, Breeze AL, Poyser JP, O’Brien R, Ladbury JE, Wigley DB: The high-resolution crystal structure of a 24-kDa gyrase B fragment from E. coli complexed with one of the most potent coumarin inhibitors, clorobiocin. Proteins. 1997 May;28(1):41-52. To Reference
Ref 51J Nat Prod. 2001 Oct;64(10):1294-6.Catalytic inhibition of topoisomerase IIalpha by demethylzeylasterone, a 6-oxophenolic triterpenoid from Kokoona zeylanica. To Reference
Ref 52Antitumor activity of ER-37328, a novel carbazole topoisomerase II inhibitor. Mol Cancer Ther. 2002 Jan;1(3):169-75. To Reference
Ref 53Overington 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 54Anticancer effect of Howiinol A and its mechanism of action. J Asian Nat Prod Res. 1999;2(1):1-19. To Reference
Ref 55Bioorg Med Chem. 2008 Apr 1;16(7):3959-68. Epub 2008 Jan 26.The structure-based design, synthesis and biological evaluation of DNA-binding bisintercalating bisanthrapyrazole anticancer compounds. To Reference
Ref 56J Nat Prod. 2001 Dec;64(12):1545-7.Screening of triterpenoids isolated from Phyllanthus flexuosus for DNA topoisomerase inhibitory activity. To Reference
Ref 57Berman 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 58Antitumor properties of podophyllotoxin and related compounds. Curr Pharm Des. 2000 Dec;6(18):1811-39. To Reference
Ref 59How many modes of action should an antibiotic have? Curr Opin Pharmacol. 2008 Oct;8(5):564-73. Epub 2008 Jul 30. To Reference
Ref 60J Nat Prod. 2001 Feb;64(2):204-7.Isoaurostatin, a novel topoisomerase inhibitor produced by Thermomonospora alba. To Reference
Ref 61J Nat Prod. 1997 Apr;60(4):408-10.Makaluvamine N: a new pyrroloiminoquinone from Zyzzya fuliginosa. To Reference
Ref 62Emerging therapies for the treatment and prevention of otitis media. Expert Opin Emerg Drugs. 2006 May;11(2):251-64. To Reference



 

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Professor in Department of Pharmacy
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