Target Information
| Target General Information | Top | |||||
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| Target ID |
T49507
(Former ID: TTDC00045)
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| Target Name |
Ephrin type-B receptor 4 (EPHB4)
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| Synonyms |
Tyrosine-protein kinase TYRO11; TYRO11; MYK1; Hepatoma transmembrane kinase; HTK
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| Gene Name |
EPHB4
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 5 Target-related Diseases | + | ||||
| 1 | Brain cancer [ICD-11: 2A00] | |||||
| 2 | Cystic/dysplastic kidney disease [ICD-11: GB8Y] | |||||
| 3 | Lung cancer [ICD-11: 2C25] | |||||
| 4 | Metastatic meninges neoplasm [ICD-11: 2D51] | |||||
| 5 | Metastatic tumour [ICD-11: 2D50-2E2Z] | |||||
| Function |
Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. 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. Together with its cognate ligand/functional ligand EFNB2 it is involved in the regulation of cell adhesion and migration, and plays a central role in heart morphogenesis, angiogenesis and blood vessel remodeling and permeability. EPHB4-mediated forward signaling controls cellular repulsion and segregation from EFNB2-expressing 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 |
MELRVLLCWASLAAALEETLLNTKLETADLKWVTFPQVDGQWEELSGLDEEQHSVRTYEV
CDVQRAPGQAHWLRTGWVPRRGAVHVYATLRFTMLECLSLPRAGRSCKETFTVFYYESDA DTATALTPAWMENPYIKVDTVAAEHLTRKRPGAEATGKVNVKTLRLGPLSKAGFYLAFQD QGACMALLSLHLFYKKCAQLTVNLTRFPETVPRELVVPVAGSCVVDAVPAPGPSPSLYCR EDGQWAEQPVTGCSCAPGFEAAEGNTKCRACAQGTFKPLSGEGSCQPCPANSHSNTIGSA VCQCRVGYFRARTDPRGAPCTTPPSAPRSVVSRLNGSSLHLEWSAPLESGGREDLTYALR CRECRPGGSCAPCGGDLTFDPGPRDLVEPWVVVRGLRPDFTYTFEVTALNGVSSLATGPV PFEPVNVTTDREVPPAVSDIRVTRSSPSSLSLAWAVPRAPSGAVLDYEVKYHEKGAEGPS SVRFLKTSENRAELRGLKRGASYLVQVRARSEAGYGPFGQEHHSQTQLDESEGWREQLAL IAGTAVVGVVLVLVVIVVAVLCLRKQSNGREAEYSDKHGQYLIGHGTKVYIDPFTYEDPN EAVREFAKEIDVSYVKIEEVIGAGEFGEVCRGRLKAPGKKESCVAIKTLKGGYTERQRRE FLSEASIMGQFEHPNIIRLEGVVTNSMPVMILTEFMENGALDSFLRLNDGQFTVIQLVGM LRGIASGMRYLAEMSYVHRDLAARNILVNSNLVCKVSDFGLSRFLEENSSDPTYTSSLGG KIPIRWTAPEAIAFRKFTSASDAWSYGIVMWEVMSFGERPYWDMSNQDVINAIEQDYRLP PPPDCPTSLHQLMLDCWQKDRNARPRFPQVVSALDKMIRNPASLKIVARENGGASHPLLD QRQPHYSAFGSVGEWLRAIKMGRYEESFAAAGFGSFELVSQISAEDLLRIGVTLAGHQKK ILASVQHMKSQAKPGTPGGTGGPAPQY 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) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | KD019 | Drug Info | Phase 2 | Non-small-cell lung cancer | [2] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | KD019 | Drug Info | [1], [3] | |||
| Inhibitor | [+] 3 Inhibitor drugs | + | ||||
| 1 | PMID19788238C66 | Drug Info | [5] | |||
| 2 | PMID23489211C20 | Drug Info | [6] | |||
| 3 | TG-100435 | 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: Dasatinib | Ligand Info | |||||
| Structure Description | Crystal Structure of Ephrin B4 (EphB4) Receptor Protein Kinase with Dasatinib | PDB:6FNM | ||||
| Method | X-ray diffraction | Resolution | 1.16 Å | Mutation | Yes | [8] |
| PDB Sequence |
KEIDVSYVKI
617 EEVIGAGEFG627 EVCRGRLKAP637 GKKESCVAIK647 TLKGGYTERQ657 RREFLSEASI 667 MGQFEHPNII677 RLEGVVTNSM687 PVMILTEFME697 NGALDSFLRL707 NDGQFTVIQL 717 VGMLRGIASG727 MRYLAEMSYV737 HRDLAARNIL747 VNSNLVCKVS757 DFGLSRFLEE 767 GKIPIRWTAP789 EAIAFRKFTS799 ASDVWSYGIV809 MWEVMSFGER819 PYWDMSNQDV 829 INAIEQDYRL839 PPPPDCPTSL849 HQLMLDCWQK859 DRNARPRFPQ869 IVSALDKMIR 879 NPASLKIVAR889
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ILE621
3.594
GLY622
4.068
VAL629
3.958
ALA645
3.229
ILE646
3.631
LYS647
3.562
GLU664
3.357
MET668
3.800
ILE677
4.193
ILE691
3.436
LEU692
4.424
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| Ligand Name: Staurosporine | Ligand Info | |||||
| Structure Description | ephB4 kinase domain inhibitor complex | PDB:2YN8 | ||||
| Method | X-ray diffraction | Resolution | 2.11 Å | Mutation | Yes | [9] |
| PDB Sequence |
KEIDVSYVKI
617 EEVIGAGEFG627 EVCRGRLKES642 CVAIKTLKGG652 YTERQRREFL662 SEASIMGQFE 672 HPNIIRLEGV682 VTNSMPVMIL692 TEFMENGALD702 SFLRLNDGQF712 TVIQLVGMLR 722 GIASGMRYLA732 EMSYVHRDLA742 ARNILVNSNL752 VCKVSDFPIR785 WTAPEAIAFR 795 KFTSASDVWS805 YGIVMWEVMS815 FGERPYWDMS825 NQDVINAIEQ835 DYRLPPPPDC 845 PTSLHQLMLD855 CWQKDRNARP865 RFPQIVSALD875 KMIRNPASLK885 IVA |
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ILE621
3.490
GLY622
3.639
ALA623
3.437
GLY624
4.940
VAL629
3.806
ALA645
3.246
LYS647
3.236
GLU664
3.396
ILE677
4.182
THR693
3.191
GLU694
2.863
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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).
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 | 2 | Degree centrality | 2.15E-04 | Betweenness centrality | 2.50E-08 |
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| Closeness centrality | 1.82E-01 | Radiality | 1.30E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 1.25E+01 | Topological coefficient | 7.67E-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 | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | Axon guidance | |||||
| PID Pathway | [+] 3 PID Pathways | + | ||||
| 1 | EPHB forward signaling | |||||
| 2 | EphrinB-EPHB pathway | |||||
| 3 | Ephrin B reverse signaling | |||||
| Reactome | [+] 3 Reactome Pathways | + | ||||
| 1 | EPH-Ephrin signaling | |||||
| 2 | EPHB-mediated forward signaling | |||||
| 3 | EPH-ephrin mediated repulsion of cells | |||||
| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | Vitamin D Receptor Pathway | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | XL647--a multitargeted tyrosine kinase inhibitor: results of a phase II study in subjects with non-small cell lung cancer who have progressed after responding to treatment with either gefitinib or erlotinib. J Thorac Oncol. 2012 Jan;7(1):219-26. | |||||
| REF 2 | ClinicalTrials.gov (NCT01487174) KD019 Versus Erlotinib in Subjects With Stage IIIB/IV Non Small Cell Lung Cancer With Progression After First- or Second-Line Chemotherapy. U.S. National Institutes of Health. | |||||
| REF 3 | Phase II study of the multitargeted tyrosine kinase inhibitor XL647 in patients with non-small-cell lung cancer. J Thorac Oncol. 2012 May;7(5):856-65. | |||||
| REF 4 | URL: 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: 1833). | |||||
| 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 | Amino acid conjugates of lithocholic acid as antagonists of the EphA2 receptor. J Med Chem. 2013 Apr 11;56(7):2936-47. | |||||
| REF 7 | Discovery of [7-(2,6-dichlorophenyl)-5-methylbenzo [1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]amine--a potent, orally active Src kinas... Bioorg Med Chem Lett. 2007 Feb 1;17(3):602-8. | |||||
| REF 8 | NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. ChemMedChem. 2018 Aug 20;13(16):1629-1633. | |||||
| REF 9 | Stability and solubility engineering of the EphB4 tyrosine kinase catalytic domain using a rationally designed synthetic library. Protein Eng Des Sel. 2013 Oct;26(10):695-704. | |||||
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