Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKNN6GC)

• DOT Name: Ephrin type-B receptor 6 (EPHB6)
• Synonyms: HEP; Tyrosine-protein kinase-defective receptor EPH-6
• Gene Name: EPHB6
• UniProt ID: EPHB6_HUMAN
• PDB ID: 7K7J
• Pfam ID: PF14575 ; PF01404 ; PF07699 ; PF00041 ; PF07714 ; PF07647
• Sequence:
  MATEGAAQLGNRVAGMVCSLWVLLLVSSVLALEEVLLDTTGETSEIGWLTYPPGGWDEVS
  VLDDQRRLTRTFEACHVAGAPPGTGQDNWLQTHFVERRGAQRAHIRLHFSVRACSSLGVS
  GGTCRETFTLYYRQAEEPDSPDSVSSWHLKRWTKVDTIAADESFPSSSSSSSSSSSAAWA
  VGPHGAGQRAGLQLNVKERSFGPLTQRGFYVAFQDTGACLALVAVRLFSYTCPAVLRSFA
  SFPETQASGAGGASLVAAVGTCVAHAEPEEDGVGGQAGGSPPRLHCNGEGKWMVAVGGCR
  CQPGYQPARGDKACQACPRGLYKSSAGNAPCSPCPARSHAPNPAAPVCPCLEGFYRASSD
  PPEAPCTGPPSAPQELWFEVQGSALMLHWRLPRELGGRGDLLFNVVCKECEGRQEPASGG
  GGTCHRCRDEVHFDPRQRGLTESRVLVGGLRAHVPYILEVQAVNGVSELSPDPPQAAAIN
  VSTSHEVPSAVPVVHQVSRASNSITVSWPQPDQTNGNILDYQLRYYDQAEDESHSFTLTS
  ETNTATVTQLSPGHIYGFQVRARTAAGHGPYGGKVYFQTLPQGELSSQLPERLSLVIGSI
  LGALAFLLLAAITVLAVVFQRKRRGTGYTEQLQQYSSPGLGVKYYIDPSTYEDPCQAIRE
  LAREVDPAYIKIEEVIGTGSFGEVRQGRLQPRGRREQTVAIQALWAGGAESLQMTFLGRA
  AVLGQFQHPNILRLEGVVTKSRPLMVLTEFMELGPLDSFLRQREGQFSSLQLVAMQRGVA
  AAMQYLSSFAFVHRSLSAHSVLVNSHLVCKVARLGHSPQGPSCLLRWAAPEVIAHGKHTT
  SSDVWSFGILMWEVMSYGERPYWDMSEQEVLNAIEQEFRLPPPPGCPPGLHLLMLDTWQK
  DRARRPHFDQLVAAFDKMIRKPDTLQAGGDPGERPSQALLTPVALDFPCLDSPQAWLSAI
  GLECYQDNFSKFGLCTFSDVAQLSLEDLPALGITLAGHQKKLLHHIQLLQQHLRQQGSVE
  V
• Function: Kinase-defective receptor for members of the ephrin-B family. Binds to ephrin-B1 and ephrin-B2. Modulates cell adhesion and migration by exerting both positive and negative effects upon stimulation with ephrin-B2. Inhibits JNK activation, T-cell receptor-induced IL-2 secretion and CD25 expression upon stimulation with ephrin-B2.
• Tissue Specificity: Expressed in brain. Expressed in non invasive breast carcinoma cell lines (at protein level). Strong expression in brain and pancreas, and weak expression in other tissues, such as heart, placenta, lung, liver, skeletal muscle and kidney. Expressed in breast non invasive tumors but not in metastatic lesions. Isoform 3 is expressed in cell lines of glioblastomas, anaplastic astrocytomas, gliosarcomas and astrocytomas. Isoform 3 is not detected in normal tissues.
• 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

16 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 type-B receptor 6 (EPHB6).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ephrin type-B receptor 6 (EPHB6).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Ephrin type-B receptor 6 (EPHB6).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Ephrin type-B receptor 6 (EPHB6).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Ephrin type-B receptor 6 (EPHB6).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Ephrin type-B receptor 6 (EPHB6).	[6]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Ephrin type-B receptor 6 (EPHB6).	[6]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Ephrin type-B receptor 6 (EPHB6).	[7]
Selenium	DM25CGV	Approved	Selenium increases the expression of Ephrin type-B receptor 6 (EPHB6).	[8]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Ephrin type-B receptor 6 (EPHB6).	[10]
Ibuprofen	DM8VCBE	Approved	Ibuprofen affects the expression of Ephrin type-B receptor 6 (EPHB6).	[11]
Rofecoxib	DM3P5DA	Approved	Rofecoxib decreases the expression of Ephrin type-B receptor 6 (EPHB6).	[11]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Ephrin type-B receptor 6 (EPHB6).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Ephrin type-B receptor 6 (EPHB6).	[14]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Ephrin type-B receptor 6 (EPHB6).	[15]
U0126	DM31OGF	Investigative	U0126 increases the expression of Ephrin type-B receptor 6 (EPHB6).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Ephrin type-B receptor 6 (EPHB6).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Ephrin type-B receptor 6 (EPHB6).	[13]

References

• [1] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [2] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [3] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [4] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [5] Inorganic arsenic exposure promotes malignant progression by HDAC6-mediated down-regulation of HTRA1. J Appl Toxicol. 2023 Aug;43(8):1214-1224. doi: 10.1002/jat.4457. Epub 2023 Mar 11.
• [6] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [7] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [8] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [9] 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.
• [10] Folate deficiency in normal human fibroblasts leads to altered expression of genes primarily linked to cell signaling, the cytoskeleton and extracellular matrix. J Nutr Biochem. 2007 Aug;18(8):541-52. doi: 10.1016/j.jnutbio.2006.11.002. Epub 2007 Feb 22.
• [11] Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [14] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [15] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.