Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZJF3ML)

• DOT Name: Ephrin type-A receptor 3 (EPHA3)
• Synonyms: EC 2.7.10.1; EPH-like kinase 4; EK4; hEK4; HEK; Human embryo kinase; Tyrosine-protein kinase TYRO4; Tyrosine-protein kinase receptor ETK1; Eph-like tyrosine kinase 1
• Gene Name: EPHA3
• UniProt ID: EPHA3_HUMAN
• PDB ID: 2GSF; 2QO2; 2QO7; 2QO9; 2QOB; 2QOC; 2QOD; 2QOF; 2QOI; 2QOK; 2QOL; 2QON; 2QOO; 2QOQ; 3DZQ; 3FXX; 3FY2; 4G2F; 4GK2; 4GK3; 4GK4; 4L0P; 4P4C; 4P5Q; 4P5Z; 4TWN; 4TWO; 6IN0
• EC Number: 2.7.10.1
• Pfam ID: PF14575 ; PF01404 ; PF07699 ; PF00041 ; PF07714 ; PF07647
• Sequence:
  MDCQLSILLLLSCSVLDSFGELIPQPSNEVNLLDSKTIQGELGWISYPSHGWEEISGVDE
  HYTPIRTYQVCNVMDHSQNNWLRTNWVPRNSAQKIYVELKFTLRDCNSIPLVLGTCKETF
  NLYYMESDDDHGVKFREHQFTKIDTIAADESFTQMDLGDRILKLNTEIREVGPVNKKGFY
  LAFQDVGACVALVSVRVYFKKCPFTVKNLAMFPDTVPMDSQSLVEVRGSCVNNSKEEDPP
  RMYCSTEGEWLVPIGKCSCNAGYEERGFMCQACRPGFYKALDGNMKCAKCPPHSSTQEDG
  SMNCRCENNYFRADKDPPSMACTRPPSSPRNVISNINETSVILDWSWPLDTGGRKDVTFN
  IICKKCGWNIKQCEPCSPNVRFLPRQFGLTNTTVTVTDLLAHTNYTFEIDAVNGVSELSS
  PPRQFAAVSITTNQAAPSPVLTIKKDRTSRNSISLSWQEPEHPNGIILDYEVKYYEKQEQ
  ETSYTILRARGTNVTISSLKPDTIYVFQIRARTAAGYGTNSRKFEFETSPDSFSISGESS
  QVVMIAISAAVAIILLTVVIYVLIGRFCGYKSKHGADEKRLHFGNGHLKLPGLRTYVDPH
  TYEDPTQAVHEFAKELDATNISIDKVVGAGEFGEVCSGRLKLPSKKEISVAIKTLKVGYT
  EKQRRDFLGEASIMGQFDHPNIIRLEGVVTKSKPVMIVTEYMENGSLDSFLRKHDAQFTV
  IQLVGMLRGIASGMKYLSDMGYVHRDLAARNILINSNLVCKVSDFGLSRVLEDDPEAAYT
  TRGGKIPIRWTSPEAIAYRKFTSASDVWSYGIVLWEVMSYGERPYWEMSNQDVIKAVDEG
  YRLPPPMDCPAALYQLMLDCWQKDRNNRPKFEQIVSILDKLIRNPGSLKIITSAAARPSN
  LLLDQSNVDITTFRTTGDWLNGVWTAHCKEIFTGVEYSSCDTIAKISTDDMKKVGVTVVG
  PQKKIISSIKALETQSKNGPVPV
• Function: Receptor tyrosine kinase which binds promiscuously membrane-bound ephrin 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. Highly promiscuous for ephrin-A ligands it binds preferentially EFNA5. Upon activation by EFNA5 regulates cell-cell adhesion, cytoskeletal organization and cell migration. Plays a role in cardiac cells migration and differentiation and regulates the formation of the atrioventricular canal and septum during development probably through activation by EFNA1. Involved in the retinotectal mapping of neurons. May also control the segregation but not the guidance of motor and sensory axons during neuromuscular circuit development.
• Tissue Specificity: Widely expressed. Highest level in placenta.
• KEGG Pathway: Axon guidance (hsa04360)
• 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

19 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-A receptor 3 (EPHA3).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ephrin type-A receptor 3 (EPHA3).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ephrin type-A receptor 3 (EPHA3).	[3]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Ephrin type-A receptor 3 (EPHA3).	[4]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Ephrin type-A receptor 3 (EPHA3).	[5]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Ephrin type-A receptor 3 (EPHA3).	[6]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Ephrin type-A receptor 3 (EPHA3).	[4]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Ephrin type-A receptor 3 (EPHA3).	[7]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Ephrin type-A receptor 3 (EPHA3).	[8]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Ephrin type-A receptor 3 (EPHA3).	[9]
Rofecoxib	DM3P5DA	Approved	Rofecoxib decreases the expression of Ephrin type-A receptor 3 (EPHA3).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Ephrin type-A receptor 3 (EPHA3).	[11]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Ephrin type-A receptor 3 (EPHA3).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Ephrin type-A receptor 3 (EPHA3).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ephrin type-A receptor 3 (EPHA3).	[12]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the activity of Ephrin type-A receptor 3 (EPHA3).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Ephrin type-A receptor 3 (EPHA3).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Ephrin type-A receptor 3 (EPHA3).	[8]
GW-788388	DMIBUW5	Investigative	GW-788388 increases the expression of Ephrin type-A receptor 3 (EPHA3).	[15]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [3] 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.
• [4] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [5] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [6] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [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] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [9] Effects of tobacco compounds on gene expression in fetal lung fibroblasts. Environ Toxicol. 2008 Aug;23(4):423-34.
• [10] Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
• [11] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [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] Discovery of 5-(arenethynyl) hetero-monocyclic derivatives as potent inhibitors of BCR-ABL including the T315I gatekeeper mutant. Bioorg Med Chem Lett. 2011 Jun 15;21(12):3743-8.
• [14] 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.
• [15] Capturing time-dependent activation of genes and stress-response pathways using transcriptomics in iPSC-derived renal proximal tubule cells. Cell Biol Toxicol. 2023 Aug;39(4):1773-1793. doi: 10.1007/s10565-022-09783-5. Epub 2022 Dec 31.