Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUIKN2I)

• DOT Name: Seizure 6-like protein 2 (SEZ6L2)
• Gene Name: SEZ6L2
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Autism
  Cerebellar ataxia
  Dementia
  Gastric cancer
  Hepatocellular carcinoma
  Lung cancer
  Mental disorder
  Neoplasm
  Stomach cancer
• UniProt ID: SE6L2_HUMAN
• Pfam ID: PF00431 ; PF00084
• Sequence:
  MGTPRAQHPPPPQLLFLILLSCPWIQGLPLKEEEILPEPGSETPTVASEALAELLHGALL
  RRGPEMGYLPGSDRDPTLATPPAGQTLAVPSLPRATEPGTGPLTTAVTPNGVRGAGPTAP
  ELLTPPPGTTAPPPPSPASPGPPLGPEGGEEETTTTIITTTTVTTTVTSPVLCNNNISEG
  EGYVESPDLGSPVSRTLGLLDCTYSIHVYPGYGIEIQVQTLNLSQEEELLVLAGGGSPGL
  APRLLANSSMLGEGQVLRSPTNRLLLHFQSPRVPRGGGFRIHYQAYLLSCGFPPRPAHGD
  VSVTDLHPGGTATFHCDSGYQLQGEETLICLNGTRPSWNGETPSCMASCGGTIHNATLGR
  IVSPEPGGAVGPNLTCRWVIEAAEGRRLHLHFERVSLDEDNDRLMVRSGGSPLSPVIYDS
  DMDDVPERGLISDAQSLYVELLSETPANPLLLSLRFEAFEEDRCFAPFLAHGNVTTTDPE
  YRPGALATFSCLPGYALEPPGPPNAIECVDPTEPHWNDTEPACKAMCGGELSEPAGVVLS
  PDWPQSYSPGQDCVWGVHVQEEKRILLQVEILNVREGDMLTLFDGDGPSARVLAQLRGPQ
  PRRRLLSSGPDLTLQFQAPPGPPNPGLGQGFVLHFKEVPRNDTCPELPPPEWGWRTASHG
  DLIRGTVLTYQCEPGYELLGSDILTCQWDLSWSAAPPACQKIMTCADPGEIANGHRTASD
  AGFPVGSHVQYRCLPGYSLEGAAMLTCYSRDTGTPKWSDRVPKCALKYEPCLNPGVPENG
  YQTLYKHHYQAGESLRFFCYEGFELIGEVTITCVPGHPSQWTSQPPLCKVTQTTDPSRQL
  EGGNLALAILLPLGLVIVLGSGVYIYYTKLQGKSLFGFSGSHSYSPITVESDFSNPLYEA
  GDTREYEVSI
• Function: May contribute to specialized endoplasmic reticulum functions in neurons.

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Autism	DISV4V1Z	Strong	Biomarker	[3]
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[4]
Dementia	DISXL1WY	Strong	Biomarker	[2]
Gastric cancer	DISXGOUK	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Lung cancer	DISCM4YA	Strong	Biomarker	[7]
Mental disorder	DIS3J5R8	Strong	Altered Expression	[8]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Stomach cancer	DISKIJSX	Strong	Biomarker	[5]

13 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 2 (SEZ6L2).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Seizure 6-like protein 2 (SEZ6L2).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Seizure 6-like protein 2 (SEZ6L2).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Seizure 6-like protein 2 (SEZ6L2).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Seizure 6-like protein 2 (SEZ6L2).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Seizure 6-like protein 2 (SEZ6L2).	[14]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Seizure 6-like protein 2 (SEZ6L2).	[15]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Seizure 6-like protein 2 (SEZ6L2).	[16]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Seizure 6-like protein 2 (SEZ6L2).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Seizure 6-like protein 2 (SEZ6L2).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Seizure 6-like protein 2 (SEZ6L2).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Seizure 6-like protein 2 (SEZ6L2).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Seizure 6-like protein 2 (SEZ6L2).	[23]

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 decreases the methylation of Seizure 6-like protein 2 (SEZ6L2).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Seizure 6-like protein 2 (SEZ6L2).	[21]

References

• [1] Specific regulation of HSPs in human tumor cell lines by PSK.In Vivo. 1997 May-Jun;11(3):261-4.
• [2] Prostate-derived sterile 20-like kinases (PSKs/TAOKs) phosphorylate tau protein and are activated in tangle-bearing neurons in Alzheimer disease.J Biol Chem. 2013 May 24;288(21):15418-29. doi: 10.1074/jbc.M112.448183. Epub 2013 Apr 12.
• [3] Association and mutation analyses of 16p11.2 autism candidate genes.PLoS One. 2009;4(2):e4582. doi: 10.1371/journal.pone.0004582. Epub 2009 Feb 26.
• [4] Sez6l2 regulates phosphorylation of ADD and neuritogenesis.Biochem Biophys Res Commun. 2017 Dec 9;494(1-2):234-241. doi: 10.1016/j.bbrc.2017.10.047. Epub 2017 Oct 12.
• [5] A protein-bound polysaccharide, PSK, enhances tumor suppression induced by docetaxel in a gastric cancer xenograft model.Anticancer Res. 2009 Mar;29(3):843-50.
• [6] An integrated data analysis approach to characterize genes highly expressed in hepatocellular carcinoma.Oncogene. 2005 May 26;24(23):3737-47. doi: 10.1038/sj.onc.1208479.
• [7] Characterization of SEZ6L2 cell-surface protein as a novel prognostic marker for lung cancer.Cancer Sci. 2006 Aug;97(8):737-45. doi: 10.1111/j.1349-7006.2006.00258.x.
• [8] 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.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] Cyclosporine A--induced oxidative stress in human renal mesangial cells: a role for ERK 1/2 MAPK signaling. Toxicol Sci. 2012 Mar;126(1):101-13.
• [11] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [12] 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.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] 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.
• [15] 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.
• [16] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [17] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [23] Identification of formaldehyde-responsive genes by suppression subtractive hybridization. Toxicology. 2008 Jan 14;243(1-2):224-35.