Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT12WTXQ)

• DOT Name: Ephrin-B3 (EFNB3)
• Synonyms: EPH-related receptor transmembrane ligand ELK-L3; EPH-related receptor tyrosine kinase ligand 8; LERK-8
• Gene Name: EFNB3
• Related Disease:
  B-cell neoplasm
  Non-insulin dependent diabetes
  Vascular disease
  Adult glioblastoma
  Advanced cancer
  Epilepsy
  Glioblastoma multiforme
  High blood pressure
  Hypogonadism
  Neoplasm
  Non-small-cell lung cancer
  Status epilepticus seizure
  Glioma
  Neuroblastoma
• UniProt ID: EFNB3_HUMAN
• PDB ID: 4BKF
• Pfam ID: PF00812
• Sequence:
  MGPPHSGPGGVRVGALLLLGVLGLVSGLSLEPVYWNSANKRFQAEGGYVLYPQIGDRLDL
  LCPRARPPGPHSSPNYEFYKLYLVGGAQGRRCEAPPAPNLLLTCDRPDLDLRFTIKFQEY
  SPNLWGHEFRSHHDYYIIATSDGTREGLESLQGGVCLTRGMKVLLRVGQSPRGGAVPRKP
  VSEMPMERDRGAAHSLEPGKENLPGDPTSNATSRGAEGPLPPPSMPAVAGAAGGLALLLL
  GVAGAGGAMCWRRRRAKPSESRHPGPGSFGRGGSLGLGGGGGMGPREAEPGELGIALRGG
  GAADPPFCPHYEKVSGDYGHPVYIVQDGPPQSPPNIYYKV
• Function: Cell surface transmembrane ligand for Eph receptors, a family of receptor tyrosine kinases which are crucial for migration, repulsion and adhesion during neuronal, vascular and epithelial development. Binds promiscuously Eph receptors 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. May play a pivotal role in forebrain function. Binds to, and induce the collapse of, commissural axons/growth cones in vitro. May play a role in constraining the orientation of longitudinally projecting axons; (Microbial infection) Acts as a receptor for nipah virus and hendra virus.
• Tissue Specificity: Highly expressed in brain; expressed in embryonic floor plate, roof plate and hindbrain segments.
• 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

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell neoplasm	DISVY326	Definitive	Biomarker	[1]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Genetic Variation	[2]
Vascular disease	DISVS67S	Definitive	Genetic Variation	[2]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Epilepsy	DISBB28L	Strong	Biomarker	[5]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[3]
High blood pressure	DISY2OHH	Strong	Biomarker	[6]
Hypogonadism	DISICMNI	Strong	Genetic Variation	[6]
Neoplasm	DISZKGEW	Strong	Posttranslational Modification	[3]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[4]
Status epilepticus seizure	DISY3BIC	Strong	Altered Expression	[5]
Glioma	DIS5RPEH	Limited	Altered Expression	[7]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Ephrin-B3 (EFNB3) decreases the response to substance of Doxorubicin.	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Ephrin-B3 (EFNB3).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ephrin-B3 (EFNB3).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Ephrin-B3 (EFNB3).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Ephrin-B3 (EFNB3).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Ephrin-B3 (EFNB3).	[11]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Ephrin-B3 (EFNB3).	[13]
LY2835219	DM93VBZ	Approved	LY2835219 decreases the expression of Ephrin-B3 (EFNB3).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Ephrin-B3 (EFNB3).	[16]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Ephrin-B3 (EFNB3).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Ephrin-B3 (EFNB3).	[15]

References

• [1] Gene expression profile of glioblastoma multiforme invasive phenotype points to new therapeutic targets.Neoplasia. 2005 Jan;7(1):7-16. doi: 10.1593/neo.04535.
• [2] Evidence from single nucleotide polymorphism analyses of ADVANCE study demonstrates EFNB3 as a hypertension risk gene.Sci Rep. 2017 Mar 8;7:44114. doi: 10.1038/srep44114.
• [3] Ephrin-B3 supports glioblastoma growth by inhibiting apoptosis induced by the dependence receptor EphA4.Oncotarget. 2017 Apr 4;8(14):23750-23759. doi: 10.18632/oncotarget.16077.
• [4] Ephrin B3 interacts with multiple EphA receptors and drives migration and invasion in non-small cell lung cancer.Oncotarget. 2016 Sep 13;7(37):60332-60347. doi: 10.18632/oncotarget.11219.
• [5] Ephrinb3 modulates hippocampal neurogenesis and the reelin signaling pathway in a pilocarpineinduced model of epilepsy.Int J Mol Med. 2018 Jun;41(6):3457-3467. doi: 10.3892/ijmm.2018.3543. Epub 2018 Mar 7.
• [6] Analysis of the association of EPHB6, EFNB1 and EFNB3 variants with hypertension risks in males with hypogonadism.Sci Rep. 2018 Sep 27;8(1):14497. doi: 10.1038/s41598-018-32836-x.
• [7] Ephrin-B3 ligand promotes glioma invasion through activation of Rac1.Cancer Res. 2006 Sep 1;66(17):8492-500. doi: 10.1158/0008-5472.CAN-05-4211.
• [8] Destabilization of MYC/MYCN by the mitochondrial inhibitors, metaiodobenzylguanidine, metformin and phenformin.Int J Mol Med. 2014 Jan;33(1):35-42. doi: 10.3892/ijmm.2013.1545. Epub 2013 Nov 1.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [11] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [12] 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.
• [13] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [14] Biological specificity of CDK4/6 inhibitors: dose response relationship, in vivo signaling, and composite response signature. Oncotarget. 2017 Jul 4;8(27):43678-43691. doi: 10.18632/oncotarget.18435.
• [15] 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.
• [16] 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.
• [17] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [18] cDNA microarray analysis of isogenic paclitaxel- and doxorubicin-resistant breast tumor cell lines reveals distinct drug-specific genetic signatures of resistance. Breast Cancer Res Treat. 2006 Mar;96(1):17-39. doi: 10.1007/s10549-005-9026-6. Epub 2005 Dec 2.