Details of Drug Off-Target (DOT)

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

• DOT Name: Ephrin-A2 (EFNA2)
• Synonyms: EPH-related receptor tyrosine kinase ligand 6; LERK-6; HEK7 ligand; HEK7-L
• Gene Name: EFNA2
• Related Disease:
  Benign prostatic hyperplasia
  Cervical cancer
  Cervical carcinoma
  Prostate cancer
  Prostate carcinoma
  Breast cancer
  Breast carcinoma
  Chronic granulomatous disease
  Endometrial carcinoma
  Gastric cancer
  Lupus
  Pancreatic cancer
  Retinoblastoma
  Stomach cancer
  Systemic lupus erythematosus
  Advanced cancer
  Neoplasm
  Acute myelogenous leukaemia
  Digestive system neoplasm
  Glioblastoma multiforme
  Nasopharyngeal carcinoma
• UniProt ID: EFNA2_HUMAN
• PDB ID: 2WO3
• Pfam ID: PF00812
• Sequence:
  MAPAQRPLLPLLLLLLPLPPPPFARAEDAARANSDRYAVYWNRSNPRFHAGAGDDGGGYT
  VEVSINDYLDIYCPHYGAPLPPAERMEHYVLYMVNGEGHASCDHRQRGFKRWECNRPAAP
  GGPLKFSEKFQLFTPFSLGFEFRPGHEYYYISATPPNAVDRPCLRLKVYVRPTNETLYEA
  PEPIFTSNNSCSSPGGCRLFLSTIPVLWTLLGS
• 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. With the EPHA2 receptor may play a role in bone remodeling through regulation of osteoclastogenesis and osteoblastogenesis.
• 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

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Benign prostatic hyperplasia	DISI3CW2	Definitive	Biomarker	[1]
Cervical cancer	DISFSHPF	Definitive	Altered Expression	[2]
Cervical carcinoma	DIST4S00	Definitive	Altered Expression	[2]
Prostate cancer	DISF190Y	Definitive	Biomarker	[1]
Prostate carcinoma	DISMJPLE	Definitive	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Chronic granulomatous disease	DIS9ZR24	Strong	Genetic Variation	[4]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[5]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[6]
Lupus	DISOKJWA	Strong	Biomarker	[7]
Pancreatic cancer	DISJC981	Strong	Biomarker	[8]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[2]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[6]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[7]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[9]
Neoplasm	DISZKGEW	moderate	Altered Expression	[9]
Acute myelogenous leukaemia	DISCSPTN	Limited	Biomarker	[10]
Digestive system neoplasm	DISPOJCT	Limited	Altered Expression	[11]
Glioblastoma multiforme	DISK8246	Limited	Altered Expression	[12]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Ephrin-A2 (EFNA2).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Ephrin-A2 (EFNA2).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Ephrin-A2 (EFNA2).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ephrin-A2 (EFNA2).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Ephrin-A2 (EFNA2).	[17]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Ephrin-A2 (EFNA2).	[18]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Ephrin-A2 (EFNA2).	[19]
Melphalan	DMOLNHF	Approved	Melphalan increases the expression of Ephrin-A2 (EFNA2).	[20]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Ephrin-A2 (EFNA2).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Ephrin-A2 (EFNA2).	[23]

References

• [1] Diagnostic and prognostic value of tissue and circulating levels of Ephrin-A2 in prostate cancer.Tumour Biol. 2016 Apr;37(4):5365-74. doi: 10.1007/s13277-015-4398-7. Epub 2015 Nov 11.
• [2] Human papilloma virus (HPV) E7-mediated attenuation of retinoblastoma (Rb) induces hPygopus2 expression via Elf-1 in cervical cancer.Mol Cancer Res. 2013 Jan;11(1):19-30. doi: 10.1158/1541-7786.MCR-12-0510. Epub 2013 Jan 2.
• [3] Protein expression of the Ets transcription factor Elf-1 in breast cancer cells is negatively correlated with histological grading, but not with clinical outcome.Oncol Rep. 2011 Nov;26(5):1121-5. doi: 10.3892/or.2011.1409. Epub 2011 Aug 2.
• [4] Elf-1 and PU.1 induce expression of gp91(phox) via a promoter element mutated in a subset of chronic granulomatous disease patients.Blood. 1999 May 15;93(10):3512-20.
• [5] The relationship between oncogene expression and clinical outcome in endometrial carcinoma.Curr Cancer Drug Targets. 2004 Sep;4(6):511-20. doi: 10.2174/1568009043332871.
• [6] Overexpression of Ephrin A2 receptors in cancer stromal cells is a prognostic factor for the relapse of gastric cancer.Gastric Cancer. 2015 Jul;18(3):485-94. doi: 10.1007/s10120-014-0390-y. Epub 2014 Jun 8.
• [7] PP2A dephosphorylates Elf-1 and determines the expression of CD3zeta and FcRgamma in human systemic lupus erythematosus T cells.J Immunol. 2008 Sep 1;181(5):3658-64. doi: 10.4049/jimmunol.181.5.3658.
• [8] Ephrin A2 receptor targeting does not increase adenoviral pancreatic cancer transduction in vivo.World J Gastroenterol. 2009 Jun 14;15(22):2754-62. doi: 10.3748/wjg.15.2754.
• [9] Structural investigation of a C-terminal EphA2 receptor mutant: Does mutation affect the structure and interaction properties of the Sam domain?.Biochim Biophys Acta Proteins Proteom. 2017 Sep;1865(9):1095-1104. doi: 10.1016/j.bbapap.2017.06.003. Epub 2017 Jun 6.
• [10] The level of MEF but not ELF-1 correlates with FAB subtype of acute myeloid leukemia and is low in good prognosis cases.Leuk Res. 2003 May;27(5):387-92. doi: 10.1016/s0145-2126(02)00214-x.
• [11] Inactivation of ELF/TGF-beta signaling in human gastrointestinal cancer.Oncogene. 2005 Dec 1;24(54):8012-24. doi: 10.1038/sj.onc.1208946.
• [12] Trivalent CAR T cells overcome interpatient antigenic variability in glioblastoma.Neuro Oncol. 2018 Mar 27;20(4):506-518. doi: 10.1093/neuonc/nox182.
• [13] ELF-1 expression in nasopharyngeal carcinoma facilitates proliferation and metastasis of cancer cells via modulation of CCL2/CCR2 signaling.Cancer Manag Res. 2019 Jun 6;11:5243-5254. doi: 10.2147/CMAR.S196355. eCollection 2019.
• [14] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [15] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [16] 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.
• [17] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [18] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [19] Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
• [20] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] 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.
• [23] 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.