Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8VZ6C5)

• DOT Name: Ephrin type-B receptor 2 (EPHB2)
• Synonyms: EC 2.7.10.1; Developmentally-regulated Eph-related tyrosine kinase; ELK-related tyrosine kinase; EPH tyrosine kinase 3; EPH-like kinase 5; EK5; hEK5; Renal carcinoma antigen NY-REN-47; Tyrosine-protein kinase TYRO5; Tyrosine-protein kinase receptor EPH-3
• Gene Name: EPHB2
• Related Disease: Bleeding disorder, platelet-type, 22
• UniProt ID: EPHB2_HUMAN
• PDB ID: 1B4F; 1F0M; 2QBX; 3ZFM; 8EBL
• EC Number: 2.7.10.1
• Pfam ID: PF14575 ; PF01404 ; PF07699 ; PF00041 ; PF07714 ; PF00536
• Sequence:
  MALRRLGAALLLLPLLAAVEETLMDSTTATAELGWMVHPPSGWEEVSGYDENMNTIRTYQ
  VCNVFESSQNNWLRTKFIRRRGAHRIHVEMKFSVRDCSSIPSVPGSCKETFNLYYYEADF
  DSATKTFPNWMENPWVKVDTIAADESFSQVDLGGRVMKINTEVRSFGPVSRSGFYLAFQD
  YGGCMSLIAVRVFYRKCPRIIQNGAIFQETLSGAESTSLVAARGSCIANAEEVDVPIKLY
  CNGDGEWLVPIGRCMCKAGFEAVENGTVCRGCPSGTFKANQGDEACTHCPINSRTTSEGA
  TNCVCRNGYYRADLDPLDMPCTTIPSAPQAVISSVNETSLMLEWTPPRDSGGREDLVYNI
  ICKSCGSGRGACTRCGDNVQYAPRQLGLTEPRIYISDLLAHTQYTFEIQAVNGVTDQSPF
  SPQFASVNITTNQAAPSAVSIMHQVSRTVDSITLSWSQPDQPNGVILDYELQYYEKELSE
  YNATAIKSPTNTVTVQGLKAGAIYVFQVRARTVAGYGRYSGKMYFQTMTEAEYQTSIQEK
  LPLIIGSSAAGLVFLIAVVVIAIVCNRRGFERADSEYTDKLQHYTSGHMTPGMKIYIDPF
  TYEDPNEAVREFAKEIDISCVKIEQVIGAGEFGEVCSGHLKLPGKREIFVAIKTLKSGYT
  EKQRRDFLSEASIMGQFDHPNVIHLEGVVTKSTPVMIITEFMENGSLDSFLRQNDGQFTV
  IQLVGMLRGIAAGMKYLADMNYVHRDLAARNILVNSNLVCKVSDFGLSRFLEDDTSDPTY
  TSALGGKIPIRWTAPEAIQYRKFTSASDVWSYGIVMWEVMSYGERPYWDMTNQDVINAIE
  QDYRLPPPMDCPSALHQLMLDCWQKDRNHRPKFGQIVNTLDKMIRNPNSLKAMAPLSSGI
  NLPLLDRTIPDYTSFNTVDEWLEAIKMGQYKESFANAGFTSFDVVSQMMMEDILRVGVTL
  AGHQKKILNSIQVMRAQMNQIQSVEGQPLARRPRATGRTKRCQPRDVTKKTCNSNDGKKK
  GMGKKKTDPGRGREIQGIFFKEDSHKESNDCSCGG
• Function: Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B 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. Functions in axon guidance during development. Involved in the guidance of commissural axons, that form a major interhemispheric connection between the 2 temporal lobes of the cerebral cortex. Also involved in guidance of contralateral inner ear efferent growth cones at the midline and of retinal ganglion cell axons to the optic disk. In addition to axon guidance, also regulates dendritic spines development and maturation and stimulates the formation of excitatory synapses. Upon activation by EFNB1, abolishes the ARHGEF15-mediated negative regulation on excitatory synapse formation. Controls other aspects of development including angiogenesis, palate development and in inner ear development through regulation of endolymph production. Forward and reverse signaling through the EFNB2/EPHB2 complex regulate movement and adhesion of cells that tubularize the urethra and septate the cloaca. May function as a tumor suppressor. May be involved in the regulation of platelet activation and blood coagulation.
• Tissue Specificity: Brain, heart, lung, kidney, placenta, pancreas, liver and skeletal muscle. Preferentially expressed in fetal brain.
• KEGG Pathway: Axon guidance (hsa04360)
• Reactome Pathway:
  L1CAM interactions (R-HSA-373760)
  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

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bleeding disorder, platelet-type, 22	DIS6JB6I	Limited	Unknown	[1]

16 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 type-B receptor 2 (EPHB2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ephrin type-B receptor 2 (EPHB2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ephrin type-B receptor 2 (EPHB2).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Ephrin type-B receptor 2 (EPHB2).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Ephrin type-B receptor 2 (EPHB2).	[7]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Ephrin type-B receptor 2 (EPHB2).	[7]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Ephrin type-B receptor 2 (EPHB2).	[8]
Propofol	DMB4OLE	Approved	Propofol increases the expression of Ephrin type-B receptor 2 (EPHB2).	[9]
Sevoflurane	DMC9O43	Approved	Sevoflurane increases the expression of Ephrin type-B receptor 2 (EPHB2).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Ephrin type-B receptor 2 (EPHB2).	[10]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Ephrin type-B receptor 2 (EPHB2).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Ephrin type-B receptor 2 (EPHB2).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Ephrin type-B receptor 2 (EPHB2).	[12]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the activity of Ephrin type-B receptor 2 (EPHB2).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Ephrin type-B receptor 2 (EPHB2).	[15]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Ephrin type-B receptor 2 (EPHB2).	[16]

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 type-B receptor 2 (EPHB2).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Ephrin type-B receptor 2 (EPHB2).	[14]

References

• [1] Towards the identification of a genetic basis for Landau-Kleffner syndrome. Epilepsia. 2014 Jun;55(6):858-65. doi: 10.1111/epi.12645. Epub 2014 May 14.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [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] 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.
• [8] 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.
• [9] The differential cancer growth associated with anaesthetics in a cancer xenograft model of mice: mechanisms and implications of postoperative cancer recurrence. Cell Biol Toxicol. 2023 Aug;39(4):1561-1575. doi: 10.1007/s10565-022-09747-9. Epub 2022 Aug 12.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.