Details of Drug Off-Target (DOT)

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

• DOT Name: Ephrin-A4 (EFNA4)
• Synonyms: EPH-related receptor tyrosine kinase ligand 4; LERK-4
• Gene Name: EFNA4
• Related Disease:
  Craniofrontonasal syndrome
  Leiomyoma
  Neoplasm
  Promyelocytic leukaemia
  Synostosis
  Triple negative breast cancer
  Uterine fibroids
  Craniosynostosis
  Small lymphocytic lymphoma
  Hepatitis C virus infection
• UniProt ID: EFNA4_HUMAN
• Pfam ID: PF00812
• Sequence:
  MRLLPLLRTVLWAAFLGSPLRGGSSLRHVVYWNSSNPRLLRGDAVVELGLNDYLDIVCPH
  YEGPGPPEGPETFALYMVDWPGYESCQAEGPRAYKRWVCSLPFGHVQFSEKIQRFTPFSL
  GFEFLPGETYYYISVPTPESSGQCLRLQVSVCCKERKSESAHPVGSPGESGTSGWRGGDT
  PSPLCLLLLLLLLILRLLRIL
• 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. May play a role in the interaction between activated B-lymphocytes and dendritic cells in tonsils.
• Tissue Specificity: Expressed in the adult spleen, lymph node, prostate, ovary, small intestine, and colon, and in fetal heart, lung, liver and kidney. Also detected in hematopoietic cell lines.
• 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

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Craniofrontonasal syndrome	DISSO9WK	Strong	Genetic Variation	[1]
Leiomyoma	DISLDDFN	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Promyelocytic leukaemia	DISYGG13	Strong	Altered Expression	[4]
Synostosis	DISXGMZW	Strong	Biomarker	[5]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[3]
Uterine fibroids	DISBZRMJ	Strong	Biomarker	[2]
Craniosynostosis	DIS6J405	moderate	Genetic Variation	[1]
Small lymphocytic lymphoma	DIS30POX	moderate	Biomarker	[6]
Hepatitis C virus infection	DISQ0M8R	Limited	Biomarker	[7]

2 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-A4 (EFNA4).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Ephrin-A4 (EFNA4).	[17]

14 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-A4 (EFNA4).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ephrin-A4 (EFNA4).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ephrin-A4 (EFNA4).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ephrin-A4 (EFNA4).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Ephrin-A4 (EFNA4).	[13]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Ephrin-A4 (EFNA4).	[14]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Ephrin-A4 (EFNA4).	[15]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Ephrin-A4 (EFNA4).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Ephrin-A4 (EFNA4).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ephrin-A4 (EFNA4).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Ephrin-A4 (EFNA4).	[20]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Ephrin-A4 (EFNA4).	[21]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Ephrin-A4 (EFNA4).	[22]
CH-223191	DMMJZYC	Investigative	CH-223191 decreases the expression of Ephrin-A4 (EFNA4).	[23]

References

• [1] Molecular Analysis of Ephrin A4 and Ephrin B1 in a Rabbit Model of Craniosynostosis: Likely Exclusion as the Loci of Origin.Cleft Palate Craniofac J. 2018 Aug;55(7):1020-1025. doi: 10.1597/16-135. Epub 2018 Feb 22.
• [2] Expression profiling of protein tyrosine kinases and their ligand activators in leiomyoma uteri.Syst Biol Reprod Med. 2010 Aug;56(4):318-26. doi: 10.3109/19396361003646109.
• [3] First-in-human, phase I study of PF-06647263, an anti-EFNA4 calicheamicin antibody-drug conjugate, in patients with advanced solid tumors.Int J Cancer. 2019 Oct 1;145(7):1798-1808. doi: 10.1002/ijc.32154. Epub 2019 Feb 23.
• [4] EphA receptors and ephrin-A ligands are upregulated by monocytic differentiation/maturation and promote cell adhesion and protrusion formation in HL60 monocytes.BMC Cell Biol. 2017 Aug 29;18(1):28. doi: 10.1186/s12860-017-0144-x.
• [5] Cell mixing at a neural crest-mesoderm boundary and deficient ephrin-Eph signaling in the pathogenesis of craniosynostosis.Hum Mol Genet. 2006 Apr 15;15(8):1319-28. doi: 10.1093/hmg/ddl052. Epub 2006 Mar 15.
• [6] Expression profile of Eph receptors and ephrin ligands in healthy human B lymphocytes and chronic lymphocytic leukemia B-cells.Leuk Res. 2009 Mar;33(3):395-406. doi: 10.1016/j.leukres.2008.08.010. Epub 2008 Sep 26.
• [7] Identification of Potential Gene Network Associated with HCV-Related Hepatocellular Carcinoma Using Microarray Analysis.Pathol Oncol Res. 2018 Jul;24(3):507-514. doi: 10.1007/s12253-017-0273-8. Epub 2017 Jul 1.
• [8] 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.
• [9] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [10] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [15] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [16] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [17] 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.
• [18] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [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] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [21] Comparison of the global gene expression profiles produced by methylparaben, n-butylparaben and 17beta-oestradiol in MCF7 human breast cancer cells. J Appl Toxicol. 2007 Jan-Feb;27(1):67-77. doi: 10.1002/jat.1200.
• [22] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [23] Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands. Toxicol Lett. 2018 Aug;292:162-174.