Target Information
| Target General Information | Top | |||||
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| Target ID |
T39231
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| Target Name |
Tankyrase-1 (TNKS-1)
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| Synonyms |
Tankyrase I; TRF1-interacting ankyrin-related ADP-ribose polymerase; TNKS1; TINF1; TIN1; TANK1; Protein poly-ADP-ribosyltransferase tankyrase-1; Poly [ADP-ribose] polymerase tankyrase-1; Poly [ADP-ribose] polymerase 5A; PARPL; PARP5A; ARTD5; ADP-ribosyltransferase diphtheria toxin-like 5
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| Gene Name |
TNKS
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Ovarian cancer [ICD-11: 2C73] | |||||
| Function |
Acts as an activator of the Wnt signaling pathway by mediating poly-ADP-ribosylation (PARsylation) of AXIN1 and AXIN2, 2 key components of the beta-catenin destruction complex: poly-ADP-ribosylated target proteins are recognized by RNF146, which mediates their ubiquitination and subsequent degradation. Also mediates PARsylation of BLZF1 and CASC3, followed by recruitment of RNF146 and subsequent ubiquitination. Mediates PARsylation of TERF1, thereby contributing to the regulation of telomere length. Involved in centrosome maturation during prometaphase by mediating PARsylation of HEPACAM2/MIKI. May also regulate vesicle trafficking and modulate the subcellular distribution of SLC2A4/GLUT4-vesicles. May be involved in spindle pole assembly through PARsylation of NUMA1. Stimulates 26S proteasome activity. Poly-ADP-ribosyltransferase involved in various processes such as Wnt signaling pathway, telomere length and vesicle trafficking.
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| BioChemical Class |
Glycosyltransferases
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| UniProt ID | ||||||
| EC Number |
EC 2.4.2.30
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| Sequence |
MAASRRSQHHHHHHQQQLQPAPGASAPPPPPPPPLSPGLAPGTTPASPTASGLAPFASPR
HGLALPEGDGSRDPPDRPRSPDPVDGTSCCSTTSTICTVAAAPVVPAVSTSSAAGVAPNP AGSGSNNSPSSSSSPTSSSSSSPSSPGSSLAESPEAAGVSSTAPLGPGAAGPGTGVPAVS GALRELLEACRNGDVSRVKRLVDAANVNAKDMAGRKSSPLHFAAGFGRKDVVEHLLQMGA NVHARDDGGLIPLHNACSFGHAEVVSLLLCQGADPNARDNWNYTPLHEAAIKGKIDVCIV LLQHGADPNIRNTDGKSALDLADPSAKAVLTGEYKKDELLEAARSGNEEKLMALLTPLNV NCHASDGRKSTPLHLAAGYNRVRIVQLLLQHGADVHAKDKGGLVPLHNACSYGHYEVTEL LLKHGACVNAMDLWQFTPLHEAASKNRVEVCSLLLSHGADPTLVNCHGKSAVDMAPTPEL RERLTYEFKGHSLLQAAREADLAKVKKTLALEIINFKQPQSHETALHCAVASLHPKRKQV TELLLRKGANVNEKNKDFMTPLHVAAERAHNDVMEVLHKHGAKMNALDTLGQTALHRAAL AGHLQTCRLLLSYGSDPSIISLQGFTAAQMGNEAVQQILSESTPIRTSDVDYRLLEASKA GDLETVKQLCSSQNVNCRDLEGRHSTPLHFAAGYNRVSVVEYLLHHGADVHAKDKGGLVP LHNACSYGHYEVAELLVRHGASVNVADLWKFTPLHEAAAKGKYEICKLLLKHGADPTKKN RDGNTPLDLVKEGDTDIQDLLRGDAALLDAAKKGCLARVQKLCTPENINCRDTQGRNSTP LHLAAGYNNLEVAEYLLEHGADVNAQDKGGLIPLHNAASYGHVDIAALLIKYNTCVNATD KWAFTPLHEAAQKGRTQLCALLLAHGADPTMKNQEGQTPLDLATADDIRALLIDAMPPEA LPTCFKPQATVVSASLISPASTPSCLSAASSIDNLTGPLAELAVGGASNAGDGAAGTERK EGEVAGLDMNISQFLKSLGLEHLRDIFETEQITLDVLADMGHEELKEIGINAYGHRHKLI KGVERLLGGQQGTNPYLTFHCVNQGTILLDLAPEDKEYQSVEEEMQSTIREHRDGGNAGG IFNRYNVIRIQKVVNKKLRERFCHRQKEVSEENHNHHNERMLFHGSPFINAIIHKGFDER HAYIGGMFGAGIYFAENSSKSNQYVYGIGGGTGCPTHKDRSCYICHRQMLFCRVTLGKSF LQFSTMKMAHAPPGHHSVIGRPSVNGLAYAEYVIYRGEQAYPEYLITYQIMKPEAPSQTA TAAEQKT Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
| 1 | PMID27841036-Compound-37 | Drug Info | Phase 2 | Ovarian cancer | [2] | |
| 2 | Stenoparib | Drug Info | Phase 2 | Ovarian cancer | [3] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 2 Inhibitor drugs | + | ||||
| 1 | PMID27841036-Compound-37 | Drug Info | [1] | |||
| 2 | Stenoparib | Drug Info | [3] | |||
| 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: Talazoparib | Ligand Info | |||||
| Structure Description | Structure of the catalytic domain of tankyrase 1 in complex with talazoparib | PDB:7KKN | ||||
| Method | X-ray diffraction | Resolution | 1.48 Å | Mutation | No | [4] |
| PDB Sequence |
GTILLDLAPE
1114 DKEYQSVEEE1124 MQSTIREHRD1134 GGNAGGIFNR1144 YNVIRIQKVV1154 NKKLRERFCH 1164 RQKEVSEENH1174 NHHNERMLFH1184 GSPFINAIIH1194 KGFDERHAGG1206 MFGAGIYFAE 1216 NSSKSNQYVY1226 GIGGGTGCPT1236 HKDRSCYICH1246 RQMLFCRVTL1256 GKSFLQFSTM 1266 KMAHAPPGHH1276 SVIGRPSVNG1286 LAYAEYVIYR1296 GEQAYPEYLI1306 TYQIMKP |
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| Ligand Name: Olaparib | Ligand Info | |||||
| Structure Description | Structure of the catalytic domain of tankyrase 1 in complex with olaparib | PDB:7KKO | ||||
| Method | X-ray diffraction | Resolution | 1.56 Å | Mutation | No | [4] |
| PDB Sequence |
GTILLDLAPE
1114 DKEYQSVEEE1124 MQSTIREHRD1134 GGNAGGIFNR1144 YNVIRIQKVV1154 NKKLRERFCH 1164 RQKEVSEENH1174 NHHNERMLFH1184 GSPFINAIIH1194 KGFDERHAYI1204 GGMFGAGIYF 1214 AENSSKSNQY1224 VYGIGGGTGC1234 PTHKDRSCYI1244 CHRQMLFCRV1254 TLGKSFLQFS 1264 TMKMAHAPPG1274 HHSVIGRPSV1284 NGLAYAEYVI1294 YRGEQAYPEY1304 LITYQIMKPE 1314
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PHE1183
3.936
HIS1184
3.341
GLY1185
2.757
SER1186
3.780
PHE1188
4.001
ALA1191
3.724
ILE1192
3.561
GLY1196
4.130
PHE1197
3.671
ASP1198
2.807
HIS1201
3.196
ALA1202
4.207
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| 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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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 | 8 | Degree centrality | 8.59E-04 | Betweenness centrality | 4.44E-04 |
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| Closeness centrality | 2.18E-01 | Radiality | 1.38E+01 | Clustering coefficient | 7.14E-02 |
| Neighborhood connectivity | 1.88E+01 | Topological coefficient | 1.39E-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 | ||||||
| References | Top | |||||
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| REF 1 | PARP inhibitors as antitumor agents: a patent update (2013-2015).Expert Opin Ther Pat. 2017 Mar;27(3):363-382. | |||||
| REF 2 | ClinicalTrials.gov (NCT03878849) Investigation of 2X-121 in Patients With Advanced Ovarian Cancer Selected by the 2X-121 DRP (PREDICT 2X-121). U.S. National Institutes of Health. | |||||
| REF 3 | Clinical pipeline report, company report or official report of Allarity Therapeutics. | |||||
| REF 4 | Dissecting the molecular determinants of clinical PARP1 inhibitor selectivity for tankyrase1. J Biol Chem. 2021 Jan-Jun;296:100251. | |||||
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