Target Information
| Target General Information | Top | |||||
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| Target ID |
T28413
(Former ID: TTDI02061)
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| Target Name |
Ephrin type-A receptor 3 (EPHA3)
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| Synonyms |
hEK4; Tyrosineprotein kinase receptor ETK1; Tyrosineprotein kinase TYRO4; Tyrosine-protein kinase receptor ETK1; Tyrosine-protein kinase TYRO4; TYRO4; Human embryo kinase; HEK; Ephrin typeA receptor 3; Ephlike tyrosine kinase 1; Eph-like tyrosine kinase 1; ETK1; ETK protein; EPHlike kinase 4; EPH-like kinase 4; EK4
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| Gene Name |
EPHA3
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 4 Target-related Diseases | + | ||||
| 1 | Acute myeloid leukaemia [ICD-11: 2A60] | |||||
| 2 | Myelodysplastic syndrome [ICD-11: 2A37] | |||||
| 3 | Malignant haematopoietic neoplasm [ICD-11: 2B33] | |||||
| 4 | Brain cancer [ICD-11: 2A00] | |||||
| Function |
The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Highly promiscuous for ephrin-A ligands it binds preferentially EFNA5. Upon activation by EFNA5 regulates cell-cell adhesion, cytoskeletal organization and cell migration. Plays a role in cardiac cells migration and differentiation and regulates the formation of the atrioventricular canal and septum during development probably through activation by EFNA1. Involved in the retinotectal mapping of neurons. May also control the segregation but not the guidance of motor and sensory axons during neuromuscular circuit development. Receptor tyrosine kinase which binds promiscuously membrane-bound ephrin family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells.
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| EC Number |
EC 2.7.10.1
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| Sequence |
MDCQLSILLLLSCSVLDSFGELIPQPSNEVNLLDSKTIQGELGWISYPSHGWEEISGVDE
HYTPIRTYQVCNVMDHSQNNWLRTNWVPRNSAQKIYVELKFTLRDCNSIPLVLGTCKETF NLYYMESDDDHGVKFREHQFTKIDTIAADESFTQMDLGDRILKLNTEIREVGPVNKKGFY LAFQDVGACVALVSVRVYFKKCPFTVKNLAMFPDTVPMDSQSLVEVRGSCVNNSKEEDPP RMYCSTEGEWLVPIGKCSCNAGYEERGFMCQACRPGFYKALDGNMKCAKCPPHSSTQEDG SMNCRCENNYFRADKDPPSMACTRPPSSPRNVISNINETSVILDWSWPLDTGGRKDVTFN IICKKCGWNIKQCEPCSPNVRFLPRQFGLTNTTVTVTDLLAHTNYTFEIDAVNGVSELSS PPRQFAAVSITTNQAAPSPVLTIKKDRTSRNSISLSWQEPEHPNGIILDYEVKYYEKQEQ ETSYTILRARGTNVTISSLKPDTIYVFQIRARTAAGYGTNSRKFEFETSPDSFSISGESS QVVMIAISAAVAIILLTVVIYVLIGRFCGYKSKHGADEKRLHFGNGHLKLPGLRTYVDPH TYEDPTQAVHEFAKELDATNISIDKVVGAGEFGEVCSGRLKLPSKKEISVAIKTLKVGYT EKQRRDFLGEASIMGQFDHPNIIRLEGVVTKSKPVMIVTEYMENGSLDSFLRKHDAQFTV IQLVGMLRGIASGMKYLSDMGYVHRDLAARNILINSNLVCKVSDFGLSRVLEDDPEAAYT TRGGKIPIRWTSPEAIAYRKFTSASDVWSYGIVLWEVMSYGERPYWEMSNQDVIKAVDEG YRLPPPMDCPAALYQLMLDCWQKDRNNRPKFEQIVSILDKLIRNPGSLKIITSAAARPSN LLLDQSNVDITTFRTTGDWLNGVWTAHCKEIFTGVEYSSCDTIAKISTDDMKKVGVTVVG PQKKIISSIKALETQSKNGPVPV 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 | Ifabotuzumab | Drug Info | Phase 2 | Acute myeloid leukaemia | [2] | |
| 2 | KB-004 | Drug Info | Phase 1/2 | Haematological malignancy | [3] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Antagonist | [+] 1 Antagonist drugs | + | ||||
| 1 | Ifabotuzumab | Drug Info | [2], [4] | |||
| Inhibitor | [+] 3 Inhibitor drugs | + | ||||
| 1 | PMID19788238C66 | Drug Info | [5] | |||
| 2 | PMID21561767C8h | Drug Info | [6] | |||
| 3 | PMID23489211C20 | Drug Info | [7] | |||
| 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: Phosphonotyrosine | Ligand Info | |||||
| Structure Description | Human EphA3 kinase and juxtamembrane region, dephosphorylated, AMP-PNP bound | PDB:2QO7 | ||||
| Method | X-ray diffraction | Resolution | 1.60 Å | Mutation | No | [8] |
| PDB Sequence |
TYVDPHTVHE
611 FAKELDATNI621 SIDKVVGAGE631 FGEVCSGRLK641 LPSKKEISVA651 IKTLKVGYTE 661 KQRRDFLGEA671 SIMGQFDHPN681 IIRLEGVVTK691 SKPVMIVTEM702 ENGSLDSFLR 712 KHDAQFTVIQ722 LVGMLRGIAS732 GMKYLSDMGY742 VHRDLAARNI752 LINSNLVCKV 762 SDFGPIRWTS792 PEAIAYRKFT802 SASDVWSYGI812 VLWEVMSYGE822 RPYWEMSNQD 832 VIKAVDEGYR842 LPPPMDCPAA852 LYQLMLDCWQ862 KDRNNRPKFE872 QIVSILDKLI 882 RNPGSLKIIT892 SPSNLLLD
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Doramapimod | Ligand Info | |||||
| Structure Description | Human EphA3 Kinase domain in complex with Birb796 | PDB:4TWN | ||||
| Method | X-ray diffraction | Resolution | 1.71 Å | Mutation | No | [9] |
| PDB Sequence |
TVHEFAKELD
617 ATNISIDKVV627 GAGEFGEVCS637 GRLKLPSKKE647 ISVAIKTLKV657 GYTEKQRRDF 667 LGEASIMGQF677 DHPNIIRLEG687 VVTKSKPVMI697 VTEYMENGSL707 DSFLRKHDAQ 717 FTVIQLVGML727 RGIASGMKYL737 SDMGYVHRDL747 AARNILINSN757 LVCKVSDFGL 767 SRKIPIRWTS792 PEAIAYRKFT802 SASDVWSYGI812 VLWEVMSYGE822 RPYWEMSNQD 832 VIKAVDEGYR842 LPPPMDCPAA852 LYQLMLDCWQ862 KDRNNRPKFE872 QIVSILDKLI 882 RNPGSLKIIT892 SNLLLD
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VAL627
4.623
VAL635
3.799
ALA651
3.930
ILE652
4.311
LYS653
3.482
GLU670
2.778
ILE673
3.536
MET674
3.615
PHE677
3.791
ILE682
3.898
ILE683
3.711
ILE697
3.722
THR699
3.589
TYR701
3.702
MET702
2.920
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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).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
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
Human Pathway Affiliation
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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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Axon guidance | hsa04360 | Affiliated Target |
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| Class: Organismal Systems => Development and regeneration | Pathway Hierarchy | ||
| Degree | 6 | Degree centrality | 6.45E-04 | Betweenness centrality | 2.09E-05 |
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| Closeness centrality | 1.91E-01 | Radiality | 1.32E+01 | Clustering coefficient | 1.33E-01 |
| Neighborhood connectivity | 9.83E+00 | Topological coefficient | 2.46E-01 | Eccentricity | 13 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | Axon guidance | |||||
| PID Pathway | [+] 2 PID Pathways | + | ||||
| 1 | EphrinA-EPHA pathway | |||||
| 2 | EPHA forward signaling | |||||
| Reactome | [+] 3 Reactome Pathways | + | ||||
| 1 | EPH-Ephrin signaling | |||||
| 2 | EPHA-mediated growth cone collapse | |||||
| 3 | EPH-ephrin mediated repulsion of cells | |||||
| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | NRF2 pathway | |||||
| References | Top | |||||
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| REF 1 | Clinical pipeline report, company report or official report of Kalobios. | |||||
| REF 2 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 3 | ClinicalTrials.gov (NCT01211691) Study of KB004 in Subjects With Hematologic Malignancies (Myelodysplastic Syndrome, MDS, Myelofibrosis, MF). U.S. National Institutes of Health. | |||||
| REF 4 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 5 | Structure-based optimization of potent and selective inhibitors of the tyrosine kinase erythropoietin producing human hepatocellular carcinoma receptor B4 (EphB4). J Med Chem. 2009 Oct 22;52(20):6433-46. | |||||
| REF 6 | Discovery of 5-(arenethynyl) hetero-monocyclic derivatives as potent inhibitors of BCR-ABL including the T315I gatekeeper mutant. Bioorg Med Chem Lett. 2011 Jun 15;21(12):3743-8. | |||||
| REF 7 | Amino acid conjugates of lithocholic acid as antagonists of the EphA2 receptor. J Med Chem. 2013 Apr 11;56(7):2936-47. | |||||
| REF 8 | Autoregulation by the juxtamembrane region of the human ephrin receptor tyrosine kinase A3 (EphA3). Structure. 2008 Jun;16(6):873-84. | |||||
| REF 9 | Structural Analysis of the Binding of Type I, I1/2, and II Inhibitors to Eph Tyrosine Kinases. ACS Med Chem Lett. 2014 Sep 29;6(1):79-83. | |||||
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