Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJC45TA)

• DOT Name: Echinoderm microtubule-associated protein-like 4 (EML4)
• Synonyms: EMAP-4; Restrictedly overexpressed proliferation-associated protein; Ropp 120
• Gene Name: EML4
• UniProt ID: EMAL4_HUMAN
• PDB ID: 4CGC
• Pfam ID: PF03451 ; PF00400
• Sequence:
  MDGFAGSLDDSISAASTSDVQDRLSALESRVQQQEDEITVLKAALADVLRRLAISEDHVA
  SVKKSVSSKGQPSPRAVIPMSCITNGSGANRKPSHTSAVSIAGKETLSSAAKSGTEKKKE
  KPQGQREKKEESHSNDQSPQIRASPSPQPSSQPLQIHRQTPESKNATPTKSIKRPSPAEK
  SHNSWENSDDSRNKLSKIPSTPKLIPKVTKTADKHKDVIINQEGEYIKMFMRGRPITMFI
  PSDVDNYDDIRTELPPEKLKLEWAYGYRGKDCRANVYLLPTGKIVYFIASVVVLFNYEER
  TQRHYLGHTDCVKCLAIHPDKIRIATGQIAGVDKDGRPLQPHVRVWDSVTLSTLQIIGLG
  TFERGVGCLDFSKADSGVHLCIIDDSNEHMLTVWDWQKKAKGAEIKTTNEVVLAVEFHPT
  DANTIITCGKSHIFFWTWSGNSLTRKQGIFGKYEKPKFVQCLAFLGNGDVLTGDSGGVML
  IWSKTTVEPTPGKGPKGVYQISKQIKAHDGSVFTLCQMRNGMLLTGGGKDRKIILWDHDL
  NPEREIEVPDQYGTIRAVAEGKADQFLVGTSRNFILRGTFNDGFQIEVQGHTDELWGLAT
  HPFKDLLLTCAQDRQVCLWNSMEHRLEWTRLVDEPGHCADFHPSGTVVAIGTHSGRWFVL
  DAETRDLVSIHTDGNEQLSVMRYSIDGTFLAVGSHDNFIYLYVVSENGRKYSRYGRCTGH
  SSYITHLDWSPDNKYIMSNSGDYEILYWDIPNGCKLIRNRSDCKDIDWTTYTCVLGFQVF
  GVWPEGSDGTDINALVRSHNRKVIAVADDFCKVHLFQYPCSKAKAPSHKYSAHSSHVTNV
  SFTHNDSHLISTGGKDMSIIQWKLVEKLSLPQNETVADTTLTKAPVSSTESVIQSNTPTP
  PPSQPLNETAEEESRISSSPTLLENSLEQTVEPSEDHSEEESEEGSGDLGEPLYEEPCNE
  ISKEQAKATLLEDQQDPSPSS
• Function: Essential for the formation and stability of microtubules (MTs). Required for the organization of the mitotic spindle and for the proper attachment of kinetochores to MTs. Promotes the recruitment of NUDC to the mitotic spindle for mitotic progression.
• KEGG Pathway:
  Pathways in cancer (hsa05200)
  Non-small cell lung cancer (hsa05223)
  PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235)
• Reactome Pathway:
  ALK mutants bind TKIs (R-HSA-9700645)
  Signaling by ALK fusions and activated point mutants (R-HSA-9725370)
  Nuclear events stimulated by ALK signaling in cancer (R-HSA-9725371)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)

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 increases the expression of Echinoderm microtubule-associated protein-like 4 (EML4).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Echinoderm microtubule-associated protein-like 4 (EML4).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Echinoderm microtubule-associated protein-like 4 (EML4).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Echinoderm microtubule-associated protein-like 4 (EML4).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Echinoderm microtubule-associated protein-like 4 (EML4).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Echinoderm microtubule-associated protein-like 4 (EML4).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Echinoderm microtubule-associated protein-like 4 (EML4).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Echinoderm microtubule-associated protein-like 4 (EML4).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Echinoderm microtubule-associated protein-like 4 (EML4).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Echinoderm microtubule-associated protein-like 4 (EML4).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Echinoderm microtubule-associated protein-like 4 (EML4).	[11]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Echinoderm microtubule-associated protein-like 4 (EML4).	[12]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Echinoderm microtubule-associated protein-like 4 (EML4).	[13]
Crizotinib	DM4F29C	Approved	Crizotinib increases the mutagenesis of Echinoderm microtubule-associated protein-like 4 (EML4).	[14]
Mecamylamine	DMGQFYB	Approved	Mecamylamine decreases the expression of Echinoderm microtubule-associated protein-like 4 (EML4).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Echinoderm microtubule-associated protein-like 4 (EML4).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Echinoderm microtubule-associated protein-like 4 (EML4).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Echinoderm microtubule-associated protein-like 4 (EML4).	[19]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Echinoderm microtubule-associated protein-like 4 (EML4).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Echinoderm microtubule-associated protein-like 4 (EML4).	[16]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Echinoderm microtubule-associated protein-like 4 (EML4).	[16]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID26882240-Compound-32	DMJS4RP	Patented	PMID26882240-Compound-32 decreases the stability of Echinoderm microtubule-associated protein-like 4 (EML4).	[17]

References

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• [2] 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.
• [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.
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• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [8] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [9] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [10] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [11] 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.
• [12] PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med. 2006 Oct 2;203(10):2351-62.
• [13] Nicotine modulates the expression of a diverse set of genes in the neuronal SH-SY5Y cell line. J Biol Chem. 2003 May 2;278(18):15633-40.
• [14] Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK. Proc Natl Acad Sci U S A. 2011 May 3;108(18):7535-40. doi: 10.1073/pnas.1019559108. Epub 2011 Apr 18.
• [15] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [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] Differential protein stability and ALK inhibitor sensitivity of EML4-ALK fusion variants. Clin Cancer Res. 2012 Sep 1;18(17):4682-90. doi: 10.1158/1078-0432.CCR-11-3260. Epub 2012 Aug 21.
• [18] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [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] Ochratoxin a lowers mRNA levels of genes encoding for key proteins of liver cell metabolism. Cancer Genomics Proteomics. 2008 Nov-Dec;5(6):319-32.