Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKLPVXJ)

• DOT Name: Ephrin type-B receptor 4 (EPHB4)
• Synonyms: EC 2.7.10.1; Hepatoma transmembrane kinase; Tyrosine-protein kinase TYRO11
• Gene Name: EPHB4
• Related Disease:
  Capillary malformation-arteriovenous malformation 2
  EPHB4-associated vascular malformation spectrum
  Lymphatic malformation 7
  Capillary malformation-arteriovenous malformation syndrome
• UniProt ID: EPHB4_HUMAN
• PDB ID: 2BBA; 2E7H; 2HLE; 2QKQ; 2VWU; 2VWV; 2VWW; 2VWX; 2VWY; 2VWZ; 2VX0; 2VX1; 2X9F; 2XVD; 2YN8; 3ZEW; 4AW5; 4BB4; 6FNI; 6FNJ; 6FNK; 6FNL; 6FNM
• EC Number: 2.7.10.1
• Pfam ID: PF14575 ; PF01404 ; PF07699 ; PF00041 ; PF07714 ; PF00536
• Sequence:
  MELRVLLCWASLAAALEETLLNTKLETADLKWVTFPQVDGQWEELSGLDEEQHSVRTYEV
  CDVQRAPGQAHWLRTGWVPRRGAVHVYATLRFTMLECLSLPRAGRSCKETFTVFYYESDA
  DTATALTPAWMENPYIKVDTVAAEHLTRKRPGAEATGKVNVKTLRLGPLSKAGFYLAFQD
  QGACMALLSLHLFYKKCAQLTVNLTRFPETVPRELVVPVAGSCVVDAVPAPGPSPSLYCR
  EDGQWAEQPVTGCSCAPGFEAAEGNTKCRACAQGTFKPLSGEGSCQPCPANSHSNTIGSA
  VCQCRVGYFRARTDPRGAPCTTPPSAPRSVVSRLNGSSLHLEWSAPLESGGREDLTYALR
  CRECRPGGSCAPCGGDLTFDPGPRDLVEPWVVVRGLRPDFTYTFEVTALNGVSSLATGPV
  PFEPVNVTTDREVPPAVSDIRVTRSSPSSLSLAWAVPRAPSGAVLDYEVKYHEKGAEGPS
  SVRFLKTSENRAELRGLKRGASYLVQVRARSEAGYGPFGQEHHSQTQLDESEGWREQLAL
  IAGTAVVGVVLVLVVIVVAVLCLRKQSNGREAEYSDKHGQYLIGHGTKVYIDPFTYEDPN
  EAVREFAKEIDVSYVKIEEVIGAGEFGEVCRGRLKAPGKKESCVAIKTLKGGYTERQRRE
  FLSEASIMGQFEHPNIIRLEGVVTNSMPVMILTEFMENGALDSFLRLNDGQFTVIQLVGM
  LRGIASGMRYLAEMSYVHRDLAARNILVNSNLVCKVSDFGLSRFLEENSSDPTYTSSLGG
  KIPIRWTAPEAIAFRKFTSASDAWSYGIVMWEVMSFGERPYWDMSNQDVINAIEQDYRLP
  PPPDCPTSLHQLMLDCWQKDRNARPRFPQVVSALDKMIRNPASLKIVARENGGASHPLLD
  QRQPHYSAFGSVGEWLRAIKMGRYEESFAAAGFGSFELVSQISAEDLLRIGVTLAGHQKK
  ILASVQHMKSQAKPGTPGGTGGPAPQY
• 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.
• Tissue Specificity: Abundantly expressed in placenta but also detected in kidney, liver, lung, pancreas, skeletal muscle and heart. Expressed in primitive and myeloid, but not lymphoid, hematopoietic cells. Also observed in cell lines derived from liver, breast, colon, lung, melanocyte and cervix.
• KEGG Pathway: Axon guidance (hsa04360)
• Reactome Pathway:
  EPHB-mediated forward signaling (R-HSA-3928662)
  Ephrin signaling (R-HSA-3928664)
  EPH-ephrin mediated repulsion of cells (R-HSA-3928665)
  EPH-Ephrin signaling (R-HSA-2682334)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Capillary malformation-arteriovenous malformation 2	DISWKD3H	Definitive	Autosomal dominant	[1]
EPHB4-associated vascular malformation spectrum	DIS5V645	Definitive	Autosomal dominant	[2]
Lymphatic malformation 7	DISHAYGV	Strong	Autosomal dominant	[3]
Capillary malformation-arteriovenous malformation syndrome	DISMN03Q	Supportive	Autosomal dominant	[4]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Enzalutamide	DMGL19D	Approved	Ephrin type-B receptor 4 (EPHB4) affects the response to substance of Enzalutamide.	[24]

15 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ephrin type-B receptor 4 (EPHB4).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ephrin type-B receptor 4 (EPHB4).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ephrin type-B receptor 4 (EPHB4).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ephrin type-B receptor 4 (EPHB4).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Ephrin type-B receptor 4 (EPHB4).	[9]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Ephrin type-B receptor 4 (EPHB4).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Ephrin type-B receptor 4 (EPHB4).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Ephrin type-B receptor 4 (EPHB4).	[13]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Ephrin type-B receptor 4 (EPHB4).	[14]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Ephrin type-B receptor 4 (EPHB4).	[16]
Omacetaxine mepesuccinate	DMPU2WX	Approved	Omacetaxine mepesuccinate decreases the expression of Ephrin type-B receptor 4 (EPHB4).	[17]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Ephrin type-B receptor 4 (EPHB4).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Ephrin type-B receptor 4 (EPHB4).	[19]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the activity of Ephrin type-B receptor 4 (EPHB4).	[21]
SB-431542	DM0YOXQ	Preclinical	SB-431542 increases the expression of Ephrin type-B receptor 4 (EPHB4).	[22]

4 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Ephrin type-B receptor 4 (EPHB4).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Ephrin type-B receptor 4 (EPHB4).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Ephrin type-B receptor 4 (EPHB4).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Ephrin type-B receptor 4 (EPHB4).	[23]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Dasatinib	DMJV2EK	Approved	Dasatinib affects the binding of Ephrin type-B receptor 4 (EPHB4).	[15]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] EPHB4 kinase-inactivating mutations cause autosomal dominant lymphatic-related hydrops fetalis. J Clin Invest. 2016 Aug 1;126(8):3080-8. doi: 10.1172/JCI85794. Epub 2016 Jul 11.
• [4] Germline Loss-of-Function Mutations in EPHB4 Cause a Second Form of Capillary Malformation-Arteriovenous Malformation (CM-AVM2) Deregulating RAS-MAPK Signaling. Circulation. 2017 Sep 12;136(11):1037-1048. doi: 10.1161/CIRCULATIONAHA.116.026886. Epub 2017 Jul 7.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [7] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [11] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [12] Multifaceted preventive effects of single agent quercetin on a human prostate adenocarcinoma cell line (PC-3): implications for nutritional transcriptomics and multi-target therapy. Med Oncol. 2011 Dec;28(4):1395-404. doi: 10.1007/s12032-010-9603-3. Epub 2010 Jul 2.
• [13] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [14] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [15] The effects of dasatinib on IgE receptor-dependent activation and histamine release in human basophils. Blood. 2008 Mar 15;111(6):3097-107.
• [16] Gene expression in human hippocampus from cocaine abusers identifies genes which regulate extracellular matrix remodeling. PLoS One. 2007 Nov 14;2(11):e1187. doi: 10.1371/journal.pone.0001187.
• [17] Homoharringtonine suppresses LoVo cell growth by inhibiting EphB4 and the PI3K/AKT and MAPK/EKR1/2 signaling pathways. Food Chem Toxicol. 2020 Feb;136:110960. doi: 10.1016/j.fct.2019.110960. Epub 2019 Nov 11.
• [18] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [19] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [20] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [21] AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009 Nov 6;16(5):401-12. doi: 10.1016/j.ccr.2009.09.028.
• [22] Activin/nodal signaling switches the terminal fate of human embryonic stem cell-derived trophoblasts. J Biol Chem. 2015 Apr 3;290(14):8834-48.
• [23] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [24] Inhibition of the erythropoietin-producing receptor EPHB4 antagonizes androgen receptor overexpression and reduces enzalutamide resistance. J Biol Chem. 2020 Apr 17;295(16):5470-5483. doi: 10.1074/jbc.RA119.011385. Epub 2020 Mar 17.