Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGJMRZ0)

• DOT Name: Ephrin type-A receptor 1 (EPHA1)
• Synonyms: hEpha1; EC 2.7.10.1; EPH tyrosine kinase; EPH tyrosine kinase 1; Erythropoietin-producing hepatoma receptor; Tyrosine-protein kinase receptor EPH
• Gene Name: EPHA1
• UniProt ID: EPHA1_HUMAN
• PDB ID: 2K1K; 2K1L; 3HIL; 3KKA
• EC Number: 2.7.10.1
• Pfam ID: PF14575 ; PF01404 ; PF07699 ; PF00041 ; PF07714 ; PF00536
• Sequence:
  MERRWPLGLGLVLLLCAPLPPGARAKEVTLMDTSKAQGELGWLLDPPKDGWSEQQQILNG
  TPLYMYQDCPMQGRRDTDHWLRSNWIYRGEEASRVHVELQFTVRDCKSFPGGAGPLGCKE
  TFNLLYMESDQDVGIQLRRPLFQKVTTVAADQSFTIRDLVSGSVKLNVERCSLGRLTRRG
  LYLAFHNPGACVALVSVRVFYQRCPETLNGLAQFPDTLPGPAGLVEVAGTCLPHARASPR
  PSGAPRMHCSPDGEWLVPVGRCHCEPGYEEGGSGEACVACPSGSYRMDMDTPHCLTCPQQ
  STAESEGATICTCESGHYRAPGEGPQVACTGPPSAPRNLSFSASGTQLSLRWEPPADTGG
  RQDVRYSVRCSQCQGTAQDGGPCQPCGVGVHFSPGARGLTTPAVHVNGLEPYANYTFNVE
  AQNGVSGLGSSGHASTSVSISMGHAESLSGLSLRLVKKEPRQLELTWAGSRPRSPGANLT
  YELHVLNQDEERYQMVLEPRVLLTELQPDTTYIVRVRMLTPLGPGPFSPDHEFRTSPPVS
  RGLTGGEIVAVIFGLLLGAALLLGILVFRSRRAQRQRQQRQRDRATDVDREDKLWLKPYV
  DLQAYEDPAQGALDFTRELDPAWLMVDTVIGEGEFGEVYRGTLRLPSQDCKTVAIKTLKD
  TSPGGQWWNFLREATIMGQFSHPHILHLEGVVTKRKPIMIITEFMENGALDAFLREREDQ
  LVPGQLVAMLQGIASGMNYLSNHNYVHRDLAARNILVNQNLCCKVSDFGLTRLLDDFDGT
  YETQGGKIPIRWTAPEAIAHRIFTTASDVWSFGIVMWEVLSFGDKPYGEMSNQEVMKSIE
  DGYRLPPPVDCPAPLYELMKNCWAYDRARRPHFQKLQAHLEQLLANPHSLRTIANFDPRM
  TLRLPSLSGSDGIPYRTVSEWLESIRMKRYILHFHSAGLDTMECVLELTAEDLTQMGITL
  PGHQKRILCSIQGFKD
• Function: Receptor tyrosine kinase which binds promiscuously membrane-bound ephrin-A 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. Binds with a low affinity EFNA3 and EFNA4 and with a high affinity to EFNA1 which most probably constitutes its cognate/functional ligand. Upon activation by EFNA1 induces cell attachment to the extracellular matrix inhibiting cell spreading and motility through regulation of ILK and downstream RHOA and RAC. Also plays a role in angiogenesis and regulates cell proliferation. May play a role in apoptosis.
• Tissue Specificity: Overexpressed in several carcinomas.
• KEGG Pathway: Axon guidance (hsa04360)
• Reactome Pathway:
  POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation (R-HSA-2892247)
  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 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 type-A receptor 1 (EPHA1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ephrin type-A receptor 1 (EPHA1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ephrin type-A receptor 1 (EPHA1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ephrin type-A receptor 1 (EPHA1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Ephrin type-A receptor 1 (EPHA1).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Ephrin type-A receptor 1 (EPHA1).	[7]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Ephrin type-A receptor 1 (EPHA1).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Ephrin type-A receptor 1 (EPHA1).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Ephrin type-A receptor 1 (EPHA1).	[9]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of Ephrin type-A receptor 1 (EPHA1).	[5]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Ephrin type-A receptor 1 (EPHA1).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Ephrin type-A receptor 1 (EPHA1).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Ephrin type-A receptor 1 (EPHA1).	[12]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Ephrin type-A receptor 1 (EPHA1).	[5]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Ephrin type-A receptor 1 (EPHA1).	[12]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of Ephrin type-A receptor 1 (EPHA1).	[5]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Ephrin type-A receptor 1 (EPHA1).	[15]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the activity of Ephrin type-A receptor 1 (EPHA1).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Ephrin type-A receptor 1 (EPHA1).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Ephrin type-A receptor 1 (EPHA1).	[20]
GW7604	DMCA4RM	Investigative	GW7604 increases the expression of Ephrin type-A receptor 1 (EPHA1).	[5]

5 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-A receptor 1 (EPHA1).	[6]
Rigosertib	DMOSTXF	Phase 3	Rigosertib increases the phosphorylation of Ephrin type-A receptor 1 (EPHA1).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Ephrin type-A receptor 1 (EPHA1).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Ephrin type-A receptor 1 (EPHA1).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Ephrin type-A receptor 1 (EPHA1).	[18]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Gene expression profiles with activation of the estrogen receptor alpha-selective estrogen receptor modulator complex in breast cancer cells expressing wild-type estrogen receptor. Cancer Res. 2002 Aug 1;62(15):4419-26.
• [6] 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.
• [7] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [8] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [9] Epigenetic silencing of EphA1 expression in colorectal cancer is correlated with poor survival. Br J Cancer. 2009 Apr 7;100(7):1095-102. doi: 10.1038/sj.bjc.6604970. Epub 2009 Mar 10.
• [10] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] 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.
• [13] Rigosertib as a selective anti-tumor agent can ameliorate multiple dysregulated signaling transduction pathways in high-grade myelodysplastic syndrome. Sci Rep. 2014 Dec 4;4:7310. doi: 10.1038/srep07310.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.