Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOH4DRR)

• DOT Name: Ephrin-A5 (EFNA5)
• Synonyms: AL-1; EPH-related receptor tyrosine kinase ligand 7; LERK-7
• Gene Name: EFNA5
• Related Disease:
  Abdominal aortic aneurysm
  Advanced cancer
  Alzheimer disease
  Anencephaly
  Atrial fibrillation
  B-cell lymphoma
  Breast cancer
  Breast carcinoma
  Cardiac disease
  Cataract
  Cerebral palsy
  Chondrosarcoma
  Colitis
  Congenital hypothyroidism
  Cystic fibrosis
  Disease of orbital part of eye adnexa
  Gastric ulcer
  Hepatocellular carcinoma
  Hypothyroidism
  Medulloblastoma
  Obsessive compulsive disorder
  Prostate cancer
  Prostate carcinoma
  Stroke
  Synovitis
  Systemic lupus erythematosus
  Thrombocytopenia
  Ulcerative colitis
  Sclerocornea
  Coronary atherosclerosis
  Coronary heart disease
  Hypobetalipoproteinemia
  Acute myelogenous leukaemia
  Amyotrophic lateral sclerosis
  Conduct disorder
  Schizophrenia
• UniProt ID: EFNA5_HUMAN
• PDB ID: 2X11; 3MX0; 4BK5; 4BKA; 4L0P; 4M4R
• Pfam ID: PF00812
• Sequence:
  MLHVEMLTLVFLVLWMCVFSQDPGSKAVADRYAVYWNSSNPRFQRGDYHIDVCINDYLDV
  FCPHYEDSVPEDKTERYVLYMVNFDGYSACDHTSKGFKRWECNRPHSPNGPLKFSEKFQL
  FTPFSLGFEFRPGREYFYISSAIPDNGRRSCLKLKVFVRPTNSCMKTIGVHDRVFDVNDK
  VENSLEPADDTVHESAEPSRGENAAQTPRIPSRLLAILLFLLAMLLTL
• Function: Cell surface GPI-bound 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. Induces compartmentalized signaling within a caveolae-like membrane microdomain when bound to the extracellular domain of its cognate receptor. This signaling event requires the activity of the Fyn tyrosine kinase. Activates the EPHA3 receptor to regulate cell-cell adhesion and cytoskeletal organization. With the receptor EPHA2 may regulate lens fiber cells shape and interactions and be important for lens transparency maintenance. May function actively to stimulate axon fasciculation. The interaction of EFNA5 with EPHA5 also mediates communication between pancreatic islet cells to regulate glucose-stimulated insulin secretion. Cognate/functional ligand for EPHA7, their interaction regulates brain development modulating cell-cell adhesion and repulsion.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  PI3K-Akt sig.ling pathway (hsa04151)
  Axon guidance (hsa04360)
  MicroR.s in cancer (hsa05206)
• Reactome Pathway:
  EPHA-mediated growth cone collapse (R-HSA-3928663)
  EPH-ephrin mediated repulsion of cells (R-HSA-3928665)
  EPH-Ephrin signaling (R-HSA-2682334)

Molecular Interaction Atlas (MIA) of This DOT

36 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Abdominal aortic aneurysm	DISD06OF	Strong	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Anencephaly	DISIYW6T	Strong	Biomarker	[4]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[5]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Cardiac disease	DISVO1I5	Strong	Biomarker	[8]
Cataract	DISUD7SL	Strong	Genetic Variation	[9]
Cerebral palsy	DIS82ODL	Strong	Biomarker	[10]
Chondrosarcoma	DIS4I7JB	Strong	Altered Expression	[11]
Colitis	DISAF7DD	Strong	Biomarker	[12]
Congenital hypothyroidism	DISL5XVU	Strong	Altered Expression	[13]
Cystic fibrosis	DIS2OK1Q	Strong	Genetic Variation	[14]
Disease of orbital part of eye adnexa	DISGWPWX	Strong	Biomarker	[5]
Gastric ulcer	DISBBGVO	Strong	Biomarker	[15]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[16]
Hypothyroidism	DISR0H6D	Strong	Altered Expression	[13]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[17]
Obsessive compulsive disorder	DIS1ZMM2	Strong	Biomarker	[18]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[19]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[19]
Stroke	DISX6UHX	Strong	Genetic Variation	[5]
Synovitis	DISW2GPY	Strong	Biomarker	[15]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[20]
Thrombocytopenia	DISU61YW	Strong	Genetic Variation	[21]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[22]
Sclerocornea	DIS7HV8A	moderate	Biomarker	[23]
Coronary atherosclerosis	DISKNDYU	Disputed	Biomarker	[24]
Coronary heart disease	DIS5OIP1	Disputed	Biomarker	[24]
Hypobetalipoproteinemia	DIS0TPI3	Disputed	Biomarker	[25]
Acute myelogenous leukaemia	DISCSPTN	Limited	Altered Expression	[26]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Altered Expression	[27]
Conduct disorder	DISOLUZ1	Limited	Biomarker	[28]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Ephrin-A5 (EFNA5).	[30]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ephrin-A5 (EFNA5).	[31]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ephrin-A5 (EFNA5).	[32]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Ephrin-A5 (EFNA5).	[33]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Ephrin-A5 (EFNA5).	[35]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Ephrin-A5 (EFNA5).	[36]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of Ephrin-A5 (EFNA5).	[37]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Ephrin-A5 (EFNA5).	[38]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Ephrin-A5 (EFNA5).	[36]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Ephrin-A5 (EFNA5).	[40]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Ephrin-A5 (EFNA5).	[41]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Ephrin-A5 (EFNA5).	[42]

2 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-A5 (EFNA5).	[34]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Ephrin-A5 (EFNA5).	[39]

References

• [1] Differential gene expression in human abdominal aorta: aneurysmal versus occlusive disease.J Vasc Surg. 2002 Feb;35(2):346-55. doi: 10.1067/mva.2002.121071.
• [2] A naturally occurring cancer with molecular connectivity to human diseases.Cell Cycle. 2008 Aug;7(15):2286-9. doi: 10.4161/cc.6366. Epub 2008 May 29.
• [3] Candidate gene discovery procedure after follow-up confirmatory analyses of candidate regions of interests for Alzheimer's disease in the NIMH sibling dataset.Dis Markers. 2008;24(6):293-309. doi: 10.1155/2008/736409.
• [4] Regulation of repulsion versus adhesion by different splice forms of an Eph receptor.Nature. 2000 Nov 9;408(6809):203-6. doi: 10.1038/35041577.
• [5] Stroke Risk and Treatment in Patients with Atrial Fibrillation and Low CHA(2)DS(2)-VASc Scores: Findings From the ORBIT-AF I and II Registries.J Am Heart Assoc. 2018 Aug 21;7(16):e008764. doi: 10.1161/JAHA.118.008764.
• [6] Screening of key genes associated with RCHOP immunochemotherapy and construction of a prognostic risk model in diffuse large Bcell lymphoma.Mol Med Rep. 2019 Oct;20(4):3679-3690. doi: 10.3892/mmr.2019.10627. Epub 2019 Aug 29.
• [7] Resident Breast T Cells: The Troops Are Already There.Trends Mol Med. 2018 Oct;24(10):821-822. doi: 10.1016/j.molmed.2018.07.006. Epub 2018 Aug 1.
• [8] Comment on Giuseppe Genchi et al. Mercury Exposure and Heart Diseases. Int. J. Environ. Res. Public Health 2017, 14, 74.Int J Environ Res Public Health. 2017 Jul 6;14(7):733. doi: 10.3390/ijerph14070733.
• [9] Epha2 and Efna5 participate in lens cell pattern-formation.Differentiation. 2018 Jul-Aug;102:1-9. doi: 10.1016/j.diff.2018.05.002. Epub 2018 May 17.
• [10] A Model of Perinatal Ischemic Stroke in the Rat: 20 Years Already and What Lessons?.Front Neurol. 2018 Aug 7;9:650. doi: 10.3389/fneur.2018.00650. eCollection 2018.
• [11] Down-regulation of ephrin-A5, a gene product of normal cartilage, in chondrosarcoma.Hum Pathol. 2009 Dec;40(12):1679-85. doi: 10.1016/j.humpath.2009.03.024. Epub 2009 Aug 19.
• [12] Andrographolide Derivative AL-1 Ameliorates Dextran Sodium Sulfate-Induced Murine Colitis by Inhibiting NF-B and MAPK Signaling Pathways.Oxid Med Cell Longev. 2019 Oct 7;2019:6138723. doi: 10.1155/2019/6138723. eCollection 2019.
• [13] Abnormal expression of ephrin-A5 affects brain development of congenital hypothyroidism rats.Neuroreport. 2018 Aug 1;29(11):877-882. doi: 10.1097/WNR.0000000000001047.
• [14] Correction of the CF defect by curcumin: hypes and disappointments.Bioessays. 2005 Jan;27(1):9-13. doi: 10.1002/bies.20168.
• [15] Transgenic domestic animals provide an animal model for rheumatoid arthritis.Med Hypotheses. 1992 Jul;38(3):240-3. doi: 10.1016/0306-9877(92)90102-i.
• [16] Trans-dominant inhibition of transcription activator LFB1.Nucleic Acids Res. 1992 Oct 25;20(20):5321-8. doi: 10.1093/nar/20.20.5321.
• [17] Effects of altered ephrin-A5 and EphA4/EphA7 expression on tumor growth in a medulloblastoma mouse model.J Hematol Oncol. 2015 Sep 7;8:105. doi: 10.1186/s13045-015-0202-9.
• [18] Comments on: "Transcranial Direct Current Stimulation for Obsessive-Compulsive Disorder: A Systematic Review".Brain Sci. 2018 Mar 27;8(4):55. doi: 10.3390/brainsci8040055.
• [19] Novel biomarkers for prostate cancer including noncoding transcripts.Am J Pathol. 2009 Dec;175(6):2264-76. doi: 10.2353/ajpath.2009.080868. Epub 2009 Nov 5.
• [20] Novel genetic associations with interferon in systemic lupus erythematosus identified by replication and fine-mapping of trait-stratified genome-wide screen.Cytokine. 2020 Aug;132:154631. doi: 10.1016/j.cyto.2018.12.014. Epub 2019 Jan 24.
• [21] AML1 haploinsufficiency, gene dosage, and the predisposition to acute leukemia.Bioessays. 2000 Mar;22(3):214-8. doi: 10.1002/(SICI)1521-1878(200003)22:3<214::AID-BIES2>3.0.CO;2-I.
• [22] Effects of alpha lipoic acid and its derivative "andrographolid-lipoic acid-1" on ulcerative colitis: A systematic review with meta-analysis of animal studies.J Cell Biochem. 2019 Apr;120(4):4766-4782. doi: 10.1002/jcb.27807. Epub 2018 Oct 26.
• [23] New corneal findings in chromosome 10 deletion syndrome: report of two cases of corneal ectasia of varying severity.Semin Ophthalmol. 2015 Jan;30(1):58-61. doi: 10.3109/08820538.2013.821503. Epub 2013 Sep 30.
• [24] International trends in clinical characteristics and oral anticoagulation treatment for patients with atrial fibrillation: Results from the GARFIELD-AF, ORBIT-AF I, and ORBIT-AF II registries.Am Heart J. 2017 Dec;194:132-140. doi: 10.1016/j.ahj.2017.08.011. Epub 2017 Aug 24.
• [25] The molecular basis of truncated forms of apolipoprotein B in a kindred with compound heterozygous hypobetalipoproteinemia.J Lipid Res. 1989 Nov;30(11):1773-9.
• [26] Combination of chemotherapy and gemtuzumab ozogamicin in adult Philadelphia positive acute lymphoblastic leukemia patient harboring CD33 expression.Int J Hematol. 2008 Sep;88(2):209-211. doi: 10.1007/s12185-008-0123-2. Epub 2008 Aug 1.
• [27] Reduction of ephrin-A5 aggravates disease progression in amyotrophic lateral sclerosis.Acta Neuropathol Commun. 2019 Jul 12;7(1):114. doi: 10.1186/s40478-019-0759-6.
• [28] Family factors and sampling approach differentially influence attention deficit/hyperactivity disorder subtypes.Mol Psychiatry. 2004 Mar;9(3):260-3. doi: 10.1038/sj.mp.4001406.
• [29] Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.Am J Hum Genet. 2019 Aug 1;105(2):334-350. doi: 10.1016/j.ajhg.2019.06.012.
• [30] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [31] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [32] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [33] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [34] 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.
• [35] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [36] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [37] Arsenite and cadmium promote the development of mammary tumors. Carcinogenesis. 2020 Jul 14;41(7):1005-1014. doi: 10.1093/carcin/bgz176.
• [38] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [39] 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.
• [40] 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.
• [41] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [42] Epigenetic changes and disturbed neural development in a human embryonic stem cell-based model relating to the fetal valproate syndrome. Hum Mol Genet. 2012 Sep 15;21(18):4104-14. doi: 10.1093/hmg/dds239. Epub 2012 Jun 20.