Target Information
| Target General Information | Top | |||||
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| Target ID |
T17048
(Former ID: TTDI01972)
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| Target Name |
DNA topoisomerase II alpha (TOP2A)
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| Synonyms |
DNA topoisomerase II, alpha isozyme; DNA topoisomerase 2alpha; DNA topoisomerase 2-alpha
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| Gene Name |
TOP2A
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 3 Target-related Diseases | + | ||||
| 1 | Kaposi sarcoma [ICD-11: 2B57] | |||||
| 2 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| 3 | Acute myeloid leukaemia [ICD-11: 2A60] | |||||
| Function |
Topoisomerase II makes double-strand breaks. Essential during mitosis and meiosis for proper segregation of daughter chromosomes. May play a role in regulating the period length of ARNTL/BMAL1 transcriptional oscillation. Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands.
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| BioChemical Class |
Topoisomerase
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| UniProt ID | ||||||
| EC Number |
EC 5.6.2.3
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| Sequence |
MEVSPLQPVNENMQVNKIKKNEDAKKRLSVERIYQKKTQLEHILLRPDTYIGSVELVTQQ
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 Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| ADReCS ID | BADD_A05675 ; BADD_A06440 ; BADD_A08298 | |||||
| HIT2.0 ID | T51IKV | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 3 Clinical Trial Drugs | + | ||||
| 1 | Camsirubicin | Drug Info | Phase 2 | Soft tissue sarcoma | [2] | |
| 2 | PK1 | Drug Info | Phase 2 | Solid tumour/cancer | [1] | |
| 3 | Annamycin | Drug Info | Phase 1/2 | Acute myeloid leukaemia | [3] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 2 Inhibitor drugs | + | ||||
| 1 | Camsirubicin | Drug Info | [4] | |||
| 2 | NK314 | Drug Info | [6] | |||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | PK1 | Drug Info | [1] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Etoposide | Ligand Info | |||||
| Structure Description | Cryo-EM structure of the Human topoisomerase II alpha DNA-binding/cleavage domain in State 1 | PDB:6ZY5 | ||||
| Method | Electron microscopy | Resolution | 3.60 Å | Mutation | No | [7] |
| PDB Sequence |
NRIKGIPKLD
442 DANDAGGRNS452 TECTLILTEG462 DSAKTLAVSG472 LGVVGRDKYG482 VFPLRGKILN 492 VREASHKQIM502 ENAEINNIIK512 IVGLQYKKNY522 EDEDSLKTLR532 YGKIMIMTDQ 542 DQDGSHIKGL552 LINFIHHNWP562 SLLRHRFLEE572 FITPIVKVSK582 NKQEMAFYSL 592 PEFEEWKSST602 PNHKKWKVKY612 YKGLGTSTSK622 EAKEYFADMK632 RHRIQFKYSG 642 PEDDAAISLA652 FSKKQIDDRK662 EWLTNFMEDR672 RQRKLLGLPE682 DYLYGQTTTY 692 LTYNDFINKE702 LILFSNSDNE712 RSIPSMVDGL722 KPGQRKVLFT732 CFKRNDKREV 742 KVAQLAGSVA752 EMSSYHHGEM762 SLMMTIINLA772 QNFVGSNNLN782 LLQPIGQFGT 792 RLHGGKDSAS802 PRYIFTMLSS812 LARLLFPPKD822 DHTLKFLYDD832 NQRVEPEWYI 842 PIIPMVLING852 AEGIGTGWSC862 KIPNFDVREI872 VNNIRRLMDG882 EEPLPMLPSY 892 KNFKGTIEEL902 APNQYVISGE912 VAILNSTTIE922 ISELPVRTWT932 QTYKEQVLEP 942 MLNGTEKTPP952 LITDYREYHT962 DTTVKFVVKM972 TEEKLAEAER982 VGLHKVFKLQ 992 TSLTCNSMVL1002 FDHVGCLKKY1012 DTVLDILRDF1022 FELRLKYYGL1032 RKEWLLGMLG 1042 AESAKLNNQA1052 RFILEKIDGK1062 IIIENKPKKE1072 LIKVLIQRGY1082 DSDPVKAWKE 1092 AQQKVSGPTF1125 NYLLDMPLWY1135 LTKEKKDELC1145 RLRNEKEQEL1155 DTLKRKSPSD 1165 LWKEDLATFI1175 EELEAVEAKE1185 KQDEQVGLPG1195 KGGKAKGKKT1205 QMAEVLPSPR 1215
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: AMP-PNP | Ligand Info | |||||
| Structure Description | Human Topo IIa ATPase/AMP-PNP | PDB:1ZXM | ||||
| Method | X-ray diffraction | Resolution | 1.87 Å | Mutation | No | [8] |
| PDB Sequence |
SVERIYQKKT
38 QLEHILLRPD48 TYIGSVELVT58 QQMWVYDEDV68 GINYREVTFV78 PGLYKIFDEI 88 LVNAADNKQR98 DPKMSCIRVT108 IDPENNLISI118 WNNGKGIPVV128 EHKVEKMYVP 138 ALIFGQLLTS148 SNYDDDEKKV158 TGGRNGYGAK168 LCNIFSTKFT178 VETASREYKK 188 MFKQTWMDNM198 GRAGEMELKP208 FNGEDYTCIT218 FQPDLSKFKM228 QSLDKDIVAL 238 MVRRAYDIAG248 STKDVKVFLN258 GNKLPVKGFR268 SYVDMYLKDK278 LDETGNSLKV 288 IHEQVNHRWE298 VCLTMSEKGF308 QQISFVNSIA318 TSKGGRHVDY328 VADQIVTKLV 338 DVVKKKNAVK352 AHQVKNHMWI362 FVNALIENPT372 FDSQTKENMT382 LQPKSFGSTC 392 QLSEKFIKAA402 IGC
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GLU87
3.581
ASN91
2.909
ALA92
4.058
ASP94
4.395
ASN95
3.159
ARG98
3.681
ASN120
2.824
LYS123
4.280
GLY124
4.999
ILE125
3.404
ILE141
3.433
PHE142
3.601
THR147
3.466
SER148
2.758
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| Degree | 49 | Degree centrality | 5.26E-03 | Betweenness centrality | 5.57E-04 |
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| Closeness centrality | 2.25E-01 | Radiality | 1.40E+01 | Clustering coefficient | 4.54E-01 |
| Neighborhood connectivity | 3.84E+01 | Topological coefficient | 1.02E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-interacting Proteins | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| NetPath Pathway | [+] 2 NetPath Pathways | + | ||||
| 1 | TCR Signaling Pathway | |||||
| 2 | IL4 Signaling Pathway | |||||
| Panther Pathway | [+] 1 Panther Pathways | + | ||||
| 1 | DNA replication | |||||
| PID Pathway | [+] 1 PID Pathways | + | ||||
| 1 | Validated transcriptional targets of deltaNp63 isoforms | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | G0 and Early G1 | |||||
| WikiPathways | [+] 5 WikiPathways | + | ||||
| 1 | Retinoblastoma (RB) in Cancer | |||||
| 2 | Integrated Pancreatic Cancer Pathway | |||||
| 3 | Gastric cancer network 2 | |||||
| 4 | Gastric Cancer Network 1 | |||||
| 5 | Mitotic G1-G1/S phases | |||||
| References | Top | |||||
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| REF 1 | Phase II studies of polymer-doxorubicin (PK1, FCE28068) in the treatment of breast, lung and colorectal cancer. Int J Oncol. 2009 Jun;34(6):1629-36. | |||||
| REF 2 | Clinical pipeline report, company report or official report of Monopar Therapeutics. | |||||
| REF 3 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 4 | Clinical pipeline report, company report or official report of Monopar Therapeutics. | |||||
| REF 5 | Effect of structural modification at the 4, 3', and 2' positions of doxorubicin on topoisomerase II poisoning, apoptosis, and cytotoxicity in human melanoma cells. Arch Immunol Ther Exp (Warsz). May-Jun 2007;55(3):193-8. | |||||
| REF 6 | NK314, a topoisomerase II inhibitor that specifically targets the alpha isoform. J Biol Chem. 2008 Aug 29;283(35):23711-20. | |||||
| REF 7 | Structural basis for allosteric regulation of Human Topoisomerase IIAlpha. Nat Commun. 2021 May 20;12(1):2962. | |||||
| REF 8 | Nucleotide-dependent domain movement in the ATPase domain of a human type IIA DNA topoisomerase. J Biol Chem. 2005 Nov 4;280(44):37041-7. | |||||
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