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EPH receptor B4

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Target id: 1833

Nomenclature: EPH receptor B4

Abbreviated Name: EphB4

Family: Type XIII RTKs: Ephrin receptor family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 987 7q22.1 EPHB4 EPH receptor B4
Mouse 1 987 5 G2 Ephb4 Eph receptor B4
Previous and Unofficial Names Click here for help
HTK | Tyro11 | Developmental kinase 2 | Ephrin type-B receptor 4 | Hepatoma transmembrane kinase | Tyrosine kinase MYK-1 | MDK2
Database Links Click here for help
Alphafold P54760 (Hs), P54761 (Mm)
BRENDA 2.7.10.1
CATH/Gene3D 2.60.120.260, 2.60.40.10
ChEMBL Target CHEMBL5147 (Hs), CHEMBL4739680 (Mm)
Ensembl Gene ENSG00000196411 (Hs), ENSMUSG00000029710 (Mm)
Entrez Gene 2050 (Hs), 13846 (Mm)
Human Protein Atlas ENSG00000196411 (Hs)
KEGG Enzyme 2.7.10.1
KEGG Gene hsa:2050 (Hs), mmu:13846 (Mm)
OMIM 600011 (Hs)
Pharos P54760 (Hs)
RefSeq Nucleotide NM_004444 (Hs), NM_001159571 (Mm)
RefSeq Protein NP_004435 (Hs), NP_001153043 (Mm), NP_034274 (Mm)
UniProtKB P54760 (Hs), P54761 (Mm)
Wikipedia EPHB4 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal Structure and Thermodynamic Characterization of the EphB4 Receptor in Complex with an ephrin-B2 Antagonist Peptide Reveals the Determinants for Receptor Specificity.
PDB Id:  2BBA
Resolution:  1.65Å
Species:  Human
References:  5
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of Eph A4 receptor
PDB Id:  3CKH
Resolution:  2.8Å
Species:  Human
References:  16
Enzyme Reaction Click here for help
EC Number: 2.7.10.1

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
tesevatinib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.9 pIC50 9
⤷ pIC50 8.9 (IC50 1.4x10-9 M) [9]
compound 66 [PMID: 19788238] Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.8 pIC50 12
⤷ pIC50 8.8 (IC50 1.6x10-9 M) [12]
compound 20 [PMID: 23489211] Small molecule or natural product Click here for species-specific activity table Mm Inhibition 5.4 pIC50 10
⤷ pIC50 5.4 (IC50 4.4x10-6 M) [10]
View species-specific inhibitor tables
DiscoveRx KINOMEscan® screen Click here for help
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 6,19
Key to terms and symbols Click column headers to sort
Target used in screen: EPHB4
Ligand Sp. Type Action Value Parameter
dasatinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 9.5 pKd
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.0 pKd
PD-173955 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.9 pKd
foretinib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.9 pKd
vandetanib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.3 pKd
MLN-8054 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.3 pKd
crizotinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.2 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.2 pKd
nilotinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.1 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.1 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen Click here for help
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx

Reference: 2,8
Key to terms and symbols Click column headers to sort
Target used in screen: EphB4/EPHB4
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
dasatinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 1.2
nilotinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 11.4
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 12.5
vandetanib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 13.0
PP1 analog II Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 30.7 3.0 -3.0
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 37.6 70.0 14.0
dorsomorphin Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 37.7 20.0 -1.0
compound 56 [PMID: 8568816] Small molecule or natural product Hs Inhibitor Inhibition 43.0 19.0 -1.0
tozasertib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 46.1
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 51.0 30.0 4.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immuno Process Associations
Immuno Process:  Cellular signalling
Immuno Process:  Chemotaxis & migration
Immuno Process:  Immune regulation
Immuno Process:  T cell (activation)
Gene Expression and Pathophysiology Comments
Loss-of-function mutations in EPHB4 have been identified in patients with arteriovenous malformations [1,3].
General Comments
EPHB4 is a receptor for the ligand ephrin B2. EPHB4-ephrin B2 signalling is involved in embryonic vessel development and vascular remodelling. It is also involved in pathological vessel formation such as observed in tumour angiogenesis. In endothelial cells, the EPHB4/RAS/mTORC1 signalling pathway has been shown to promote vascular malformation [1,11,18,20]. EPHB4 is a therapeutic target in oncology [4,7,14-15,17]. Chemical agents that are designed to simultaneously modulate the activity of multiple angiogenesis pathways, including EPHB4 signalling, are in development as novel anti-cancer therapeutics (e.g. triple inhibitors of VEGFR-2, TIE-2 and EphB4 [13,21]).

References

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1. Amyere M, Revencu N, Helaers R, Pairet E, Baselga E, Cordisco M, Chung W, Dubois J, Lacour JP, Martorell L et al.. (2017) Germline Loss-of-Function Mutations in EPHB4 Cause a Second Form of Capillary Malformation-Arteriovenous Malformation (CM-AVM2) Deregulating RAS-MAPK Signaling. Circulation, 136 (11): 1037-1048. [PMID:28687708]

2. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1039-45. [PMID:22037377]

3. Bai J, Wang YJ, Liu L, Zhao YL. (2014) Ephrin B2 and EphB4 selectively mark arterial and venous vessels in cerebral arteriovenous malformation. J Int Med Res, 42 (2): 405-15. [PMID:24517927]

4. Chen Y, Zhang H, Zhang Y. (2019) Targeting receptor tyrosine kinase EphB4 in cancer therapy. Semin Cancer Biol, 56: 37-46. [PMID:28993206]

5. Chrencik JE, Brooun A, Recht MI, Kraus ML, Koolpe M, Kolatkar AR, Bruce RH, Martiny-Baron G, Widmer H, Pasquale EB et al.. (2006) Structure and thermodynamic characterization of the EphB4/Ephrin-B2 antagonist peptide complex reveals the determinants for receptor specificity. Structure, 14 (2): 321-30. [PMID:16472751]

6. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1046-51. [PMID:22037378]

7. Ferguson BD, Liu R, Rolle CE, Tan YH, Krasnoperov V, Kanteti R, Tretiakova MS, Cervantes GM, Hasina R, Hseu RD et al.. (2013) The EphB4 receptor tyrosine kinase promotes lung cancer growth: a potential novel therapeutic target. PLoS ONE, 8 (7): e67668. [PMID:23844053]

8. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem J, 451 (2): 313-28. [PMID:23398362]

9. Gendreau SB, Ventura R, Keast P, Laird AD, Yakes FM, Zhang W, Bentzien F, Cancilla B, Lutman J, Chu F et al.. (2007) Inhibition of the T790M gatekeeper mutant of the epidermal growth factor receptor by EXEL-7647. Clin Cancer Res, 13 (12): 3713-23. [PMID:17575237]

10. Incerti M, Tognolini M, Russo S, Pala D, Giorgio C, Hassan-Mohamed I, Noberini R, Pasquale EB, Vicini P, Piersanti S et al.. (2013) Amino acid conjugates of lithocholic acid as antagonists of the EphA2 receptor. J Med Chem, 56 (7): 2936-47. [PMID:23489211]

11. Kawasaki J, Aegerter S, Fevurly RD, Mammoto A, Mammoto T, Sahin M, Mably JD, Fishman SJ, Chan J. (2014) RASA1 functions in EPHB4 signaling pathway to suppress endothelial mTORC1 activity. J Clin Invest, 124 (6): 2774-84. [PMID:24837431]

12. Lafleur K, Huang D, Zhou T, Caflisch A, Nevado C. (2009) Structure-based optimization of potent and selective inhibitors of the tyrosine kinase erythropoietin producing human hepatocellular carcinoma receptor B4 (EphB4). J Med Chem, 52 (20): 6433-46. [PMID:19788238]

13. Li C, Shan Y, Sun Y, Si R, Liang L, Pan X, Wang B, Zhang J. (2017) Discovery of novel anti-angiogenesis agents. Part 7: Multitarget inhibitors of VEGFR-2, TIE-2 and EphB4. Eur J Med Chem, 141: 506-518. [PMID:29102175]

14. Merchant AA, Jorapur A, McManus A, Liu R, Krasnoperov V, Chaudhry P, Singh M, Harton L, Agajanian M, Kim M et al.. (2017) EPHB4 is a therapeutic target in AML and promotes leukemia cell survival via AKT. Blood Adv, 1 (20): 1635-1644. [PMID:29296810]

15. Neuber C, Belter B, Meister S, Hofheinz F, Bergmann R, Pietzsch HJ, Pietzsch AJ. (2018) Overexpression of Receptor Tyrosine Kinase EphB4 Triggers Tumor Growth and Hypoxia in A375 Melanoma Xenografts: Insights from Multitracer Small Animal Imaging Experiments. Molecules, 23 (2). [PMID:29462967]

16. Qin H, Shi J, Noberini R, Pasquale EB, Song J. (2008) Crystal structure and NMR binding reveal that two small molecule antagonists target the high affinity ephrin-binding channel of the EphA4 receptor. J Biol Chem, 283 (43): 29473-84. [PMID:18708347]

17. Salgia R, Kulkarni P, Gill PS. (2018) EphB4: A promising target for upper aerodigestive malignancies. Biochim Biophys Acta, 1869 (2): 128-137. [PMID:29369779]

18. Vivanti A, Ozanne A, Grondin C, Saliou G, Quevarec L, Maurey H, Aubourg P, Benachi A, Gut M, Gut I et al.. (2018) Loss of function mutations in EPHB4 are responsible for vein of Galen aneurysmal malformation. Brain, 141 (4): 979-988. [PMID:29444212]

19. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem Biol, 17 (11): 1241-9. [PMID:21095574]

20. Yu J, Streicher JL, Medne L, Krantz ID, Yan AC. (2017) EPHB4 Mutation Implicated in Capillary Malformation-Arteriovenous Malformation Syndrome: A Case Report. Pediatr Dermatol, 34 (5): e227-e230. [PMID:28730721]

21. Zhang L, Shan Y, Ji X, Zhu M, Li C, Sun Y, Si R, Pan X, Wang J, Ma W et al.. (2017) Discovery and evaluation of triple inhibitors of VEGFR-2, TIE-2 and EphB4 as anti-angiogenic and anti-cancer agents. Oncotarget, 8 (62): 104745-104760. [PMID:29285210]

How to cite this page

Type XIII RTKs: Ephrin receptor family: EPH receptor B4. Last modified on 26/02/2018. Accessed on 04/12/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=1833.