Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5Z9CUA)

• DOT Name: Seizure 6-like protein (SEZ6L)
• Gene Name: SEZ6L
• Related Disease:
  Lung neoplasm
  Neoplasm
  Non-small-cell lung cancer
  Small-cell lung cancer
  Autism spectrum disorder
  Bipolar disorder
  Lung cancer
  Lung carcinoma
  Mental disorder
  Plasma cell myeloma
  Acute myelogenous leukaemia
  Niemann-Pick disease type C
• UniProt ID: SE6L1_HUMAN
• PDB ID: 2YRA
• Pfam ID: PF00431 ; PF00084
• Sequence:
  MPAARPPAAGLRGISLFLALLLGSPAAALERDALPEGDASPLGPYLLPSGAPERGSPGKE
  HPEERVVTAPPSSSQSAEVLGELVLDGTAPSAHHDIPALSPLLPEEARPKHALPPKKKLP
  SLKQVNSARKQLRPKATSAATVQRAGSQPASQGLDLLSSSTEKPGPPGDPDPIVASEEAS
  EVPLWLDRKESAVPTTPAPLQISPFTSQPYVAHTLPQRPEPGEPGPDMAQEAPQEDTSPM
  ALMDKGENELTGSASEESQETTTSTIITTTVITTEQAPALCSVSFSNPEGYIDSSDYPLL
  PLNNFLECTYNVTVYTGYGVELQVKSVNLSDGELLSIRGVDGPTLTVLANQTLLVEGQVI
  RSPTNTISVYFRTFQDDGLGTFQLHYQAFMLSCNFPRRPDSGDVTVMDLHSGGVAHFHCH
  LGYELQGAKMLTCINASKPHWSSQEPICSAPCGGAVHNATIGRVLSPSYPENTNGSQFCI
  WTIEAPEGQKLHLHFERLLLHDKDRMTVHSGQTNKSALLYDSLQTESVPFEGLLSEGNTI
  RIEFTSDQARAASTFNIRFEAFEKGHCYEPYIQNGNFTTSDPTYNIGTIVEFTCDPGHSL
  EQGPAIIECINVRDPYWNDTEPLCRAMCGGELSAVAGVVLSPNWPEPYVEGEDCIWKIHV
  GEEKRIFLDIQFLNLSNSDILTIYDGDEVMPHILGQYLGNSGPQKLYSSTPDLTIQFHSD
  PAGLIFGKGQGFIMNYIEVSRNDSCSDLPEIQNGWKTTSHTELVRGARITYQCDPGYDIV
  GSDTLTCQWDLSWSSDPPFCEKIMYCTDPGEVDHSTRLISDPVLLVGTTIQYTCNPGFVL
  EGSSLLTCYSRETGTPIWTSRLPHCVSEESLACDNPGLPENGYQILYKRLYLPGESLTFM
  CYEGFELMGEVTIRCILGQPSHWNGPLPVCKVNQDSFEHALEVAEAAAETSLEGGNMALA
  IFIPVLIISLLLGGAYIYITRCRYYSNLRLPLMYSHPYSQITVETEFDNPIYETGETREY
  EVSI
• Function: May contribute to specialized endoplasmic reticulum functions in neurons.
• Tissue Specificity: Widely expressed, including adult and fetal brains and lungs. Not expressed in all lung cancer cell lines.

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung neoplasm	DISVARNB	Definitive	Genetic Variation	[1]
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Non-small-cell lung cancer	DIS5Y6R9	Definitive	Altered Expression	[1]
Small-cell lung cancer	DISK3LZD	Definitive	Altered Expression	[1]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[2]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[3]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[4]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[4]
Mental disorder	DIS3J5R8	Strong	Biomarker	[5]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[6]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[7]
Niemann-Pick disease type C	DIS492ZO	moderate	Biomarker	[8]

6 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 Seizure 6-like protein (SEZ6L).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Seizure 6-like protein (SEZ6L).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Seizure 6-like protein (SEZ6L).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Seizure 6-like protein (SEZ6L).	[12]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Seizure 6-like protein (SEZ6L).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Seizure 6-like protein (SEZ6L).	[15]

1 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 increases the methylation of Seizure 6-like protein (SEZ6L).	[14]

References

• [1] Seizure 6-like (SEZ6L) gene and risk for lung cancer.Cancer Res. 2007 Sep 1;67(17):8406-11. doi: 10.1158/0008-5472.CAN-06-4784.
• [2] Whole exome sequencing in extended families with autism spectrum disorder implicates four candidate genes.Hum Genet. 2015 Oct;134(10):1055-68. doi: 10.1007/s00439-015-1585-y. Epub 2015 Jul 24.
• [3] Polymorphisms in seizure 6-like gene are associated with bipolar disorder I: evidence of gene gender interaction.J Affect Disord. 2013 Feb 15;145(1):95-9. doi: 10.1016/j.jad.2012.07.017. Epub 2012 Aug 22.
• [4] Incorporation of a genetic factor into an epidemiologic model for prediction of individual risk of lung cancer: the Liverpool Lung Project.Cancer Prev Res (Phila). 2010 May;3(5):664-9. doi: 10.1158/1940-6207.CAPR-09-0141. Epub 2010 Apr 27.
• [5] Lack of Sez6 Family Proteins Impairs Motor Functions, Short-Term Memory, and Cognitive Flexibility and Alters Dendritic Spine Properties.Cereb Cortex. 2020 Apr 14;30(4):2167-2184. doi: 10.1093/cercor/bhz230.
• [6] Identification of unbalanced genome copy number abnormalities in patients with multiple myeloma by single-nucleotide polymorphism genotyping microarray analysis.Int J Hematol. 2012 Oct;96(4):492-500. doi: 10.1007/s12185-012-1171-1. Epub 2012 Sep 13.
• [7] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [8] BACE1-cleavage of Sez6 and Sez6L is elevated in Niemann-Pick type C disease mouse brains.PLoS One. 2018 Jul 6;13(7):e0200344. doi: 10.1371/journal.pone.0200344. eCollection 2018.
• [9] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [10] 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.
• [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] 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.
• [13] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [14] 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.
• [15] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.