Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOP2E01)

• DOT Name: Echinoderm microtubule-associated protein-like 1 (EML1)
• Synonyms: EMAP-1; HuEMAP-1
• Gene Name: EML1
• Related Disease:
  Band heterotopia of brain
  Congenital hydrocephalus
  Major depressive disorder
  Matthew-Wood syndrome
  Neoplasm
  Overgrowth syndrome
  Coronary heart disease
  Subcortical band heterotopia
  T-cell acute lymphoblastic leukaemia
• UniProt ID: EMAL1_HUMAN
• PDB ID: 4CI8
• Pfam ID: PF03451 ; PF00400
• Sequence:
  MEDGFSSYSSLYDTSSLLQFCNDDSASAASSMEVTDRIASLEQRVQMQEDDIQLLKSALA
  DVVRRLNITEEQQAVLNRKGPTKARPLMQTLPLRTTVNNGTVLPKKPTGSLPSPSGVRKE
  TAVPATKSNIKRTSSSERVSPGGRRESNGDSRGNRNRTGSTSSSSSGKKNSESKPKEPVF
  SAEEGYVKMFLRGRPVTMYMPKDQVDSYSLEAKVELPTKRLKLEWVYGYRGRDCRNNLYL
  LPTGETVYFIASVVVLYNVEEQLQRHYAGHNDDVKCLAVHPDRITIATGQVAGTSKDGKQ
  LPPHVRIWDSVTLNTLHVIGIGFFDRAVTCIAFSKSNGGTNLCAVDDSNDHVLSVWDWQK
  EEKLADVKCSNEAVFAADFHPTDTNIIVTCGKSHLYFWTLEGSSLNKKQGLFEKQEKPKF
  VLCVTFSENGDTITGDSSGNILVWGKGTNRISYAVQGAHEGGIFALCMLRDGTLVSGGGK
  DRKLISWSGNYQKLRKTEIPEQFGPIRTVAEGKGDVILIGTTRNFVLQGTLSGDFTPITQ
  GHTDELWGLAIHASKSQFLTCGHDKHATLWDAVGHRPVWDKIIEDPAQSSGFHPSGSVVA
  VGTLTGRWFVFDTETKDLVTVHTDGNEQLSVMRYSPDGNFLAIGSHDNCIYIYGVSDNGR
  KYTRVGKCSGHSSFITHLDWSVNSQFLVSNSGDYEILYWVPSACKQVVSVETTRDIEWAT
  YTCTLGFHVFGVWPEGSDGTDINAVCRAHEKKLLSTGDDFGKVHLFSYPCSQFRAPSHIY
  GGHSSHVTNVDFLCEDSHLISTGGKDTSIMQWRVI
• Function: Modulates the assembly and organization of the microtubule cytoskeleton, and probably plays a role in regulating the orientation of the mitotic spindle and the orientation of the plane of cell division. Required for normal proliferation of neuronal progenitor cells in the developing brain and for normal brain development. Does not affect neuron migration per se.
• Tissue Specificity: Ubiquitous; expressed in most tissues with the exception of thymus and peripheral blood lymphocytes.

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Band heterotopia of brain	DISQF9HP	Strong	Autosomal recessive	[1]
Congenital hydrocephalus	DIS7O6UL	Strong	Genetic Variation	[2]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[3]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Overgrowth syndrome	DISHK54G	Strong	Biomarker	[1]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[5]
Subcortical band heterotopia	DISHN7JS	Supportive	Autosomal recessive	[6]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Limited	Biomarker	[7]

10 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 1 (EML1).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Echinoderm microtubule-associated protein-like 1 (EML1).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Echinoderm microtubule-associated protein-like 1 (EML1).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Echinoderm microtubule-associated protein-like 1 (EML1).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Echinoderm microtubule-associated protein-like 1 (EML1).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Echinoderm microtubule-associated protein-like 1 (EML1).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Echinoderm microtubule-associated protein-like 1 (EML1).	[14]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Echinoderm microtubule-associated protein-like 1 (EML1).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Echinoderm microtubule-associated protein-like 1 (EML1).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Echinoderm microtubule-associated protein-like 1 (EML1).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Echinoderm microtubule-associated protein-like 1 (EML1).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Echinoderm microtubule-associated protein-like 1 (EML1).	[18]

References

• [1] EML1-associated brain overgrowth syndrome with ribbon-like heterotopia. Am J Med Genet C Semin Med Genet. 2019 Dec;181(4):627-637. doi: 10.1002/ajmg.c.31751. Epub 2019 Nov 11.
• [2] The genetic landscape of familial congenital hydrocephalus.Ann Neurol. 2017 Jun;81(6):890-897. doi: 10.1002/ana.24964.
• [3] GWAS and systems biology analysis of depressive symptoms among smokers from the COPDGene cohort.J Affect Disord. 2019 Jan 15;243:16-22. doi: 10.1016/j.jad.2018.09.003. Epub 2018 Sep 7.
• [4] Enhancing cytotoxic agent activity in experimental pancreatic cancer through EMAP II combination therapy.Cancer Chemother Pharmacol. 2011 Sep;68(3):571-82. doi: 10.1007/s00280-010-1514-7. Epub 2010 Nov 26.
• [5] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [6] Mutations in Eml1 lead to ectopic progenitors and neuronal heterotopia in mouse and human. Nat Neurosci. 2014 Jul;17(7):923-33. doi: 10.1038/nn.3729. Epub 2014 May 25.
• [7] Fusion of EML1 to ABL1 in T-cell acute lymphoblastic leukemia with cryptic t(9;14)(q34;q32).Blood. 2005 Jun 15;105(12):4849-52. doi: 10.1182/blood-2004-12-4897. Epub 2005 Feb 15.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] 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.
• [10] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] 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.
• [14] 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.
• [15] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [16] 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.
• [17] 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.
• [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] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.