Details of Drug Off-Target (DOT)

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

• DOT Name: Symplekin (SYMPK)
• Gene Name: SYMPK
• Related Disease:
  Colon cancer
  Colon carcinoma
  Colonic neoplasm
  Colorectal adenocarcinoma
  Colorectal cancer
  Colorectal cancer, susceptibility to, 1
  Colorectal cancer, susceptibility to, 10
  Colorectal cancer, susceptibility to, 12
  Colorectal carcinoma
  Colorectal neoplasm
  Gastric cancer
  Gastric neoplasm
  Gastroparesis
  Hereditary diffuse gastric adenocarcinoma
  Immunodeficiency
  Leber congenital amaurosis 2
  Xerophthalmia
  Dyspepsia
  Hepatitis
• UniProt ID: SYMPK_HUMAN
• PDB ID: 3O2Q; 3O2S; 3O2T; 3ODR; 3ODS; 4H3H; 4H3K; 6V4X
• Pfam ID: PF11935 ; PF12295
• Sequence:
  MASGSGDSVTRRSVASQFFTQEEGPGIDGMTTSERVVDLLNQAALITNDSKITVLKQVQE
  LIINKDPTLLDNFLDEIIAFQADKSIEVRKFVIGFIEEACKRDIELLLKLIANLNMLLRD
  ENVNVVKKAILTMTQLYKVALQWMVKSRVISELQEACWDMVSAMAGDIILLLDSDNDGIR
  THAIKFVEGLIVTLSPRMADSEIPRRQEHDISLDRIPRDHPYIQYNVLWEEGKAALEQLL
  KFMVHPAISSINLTTALGSLANIARQRPMFMSEVIQAYETLHANLPPTLAKSQVSSVRKN
  LKLHLLSVLKHPASLEFQAQITTLLVDLGTPQAEIARNMPSSKDTRKRPRDDSDSTLKKM
  KLEPNLGEDDEDKDLEPGPSGTSKASAQISGQSDTDITAEFLQPLLTPDNVANLVLISMV
  YLPEAMPASFQAIYTPVESAGTEAQIKHLARLMATQMTAAGLGPGVEQTKQCKEEPKEEK
  VVKTESVLIKRRLSAQGQAISVVGSLSSMSPLEEEAPQAKRRPEPIIPVTQPRLAGAGGR
  KKIFRLSDVLKPLTDAQVEAMKLGAVKRILRAEKAVACSGAAQVRIKILASLVTQFNSGL
  KAEVLSFILEDVRARLDLAFAWLYQEYNAYLAAGASGSLDKYEDCLIRLLSGLQEKPDQK
  DGIFTKVVLEAPLITESALEVVRKYCEDESRTYLGMSTLRDLIFKRPSRQFQYLHVLLDL
  SSHEKDKVRSQALLFIKRMYEKEQLREYVEKFALNYLQLLVHPNPPSVLFGADKDTEVAA
  PWTEETVKQCLYLYLALLPQNHKLIHELAAVYTEAIADIKRTVLRVIEQPIRGMGMNSPE
  LLLLVENCPKGAETLVTRCLHSLTDKVPPSPELVKRVRDLYHKRLPDVRFLIPVLNGLEK
  KEVIQALPKLIKLNPIVVKEVFNRLLGTQHGEGNSALSPLNPGELLIALHNIDSVKCDMK
  SIIKATNLCFAERNVYTSEVLAVVMQQLMEQSPLPMLLMRTVIQSLTMYPRLGGFVMNIL
  SRLIMKQVWKYPKVWEGFIKCCQRTKPQSFQVILQLPPQQLGAVFDKCPELREPLLAHVR
  SFTPHQQAHIPNSIMTILEASGKQEPEAKEAPAGPLEEDDLEPLTLAPAPAPRPPQDLIG
  LRLAQEKALKRQLEEEQKLKPGGVGAPSSSSPSPSPSARPGPPPSEEAMDFREEGPECET
  PGIFISMDDDSGLTEAALLDSSLEGPLPKETAAGGLTLKEERSPQTLAPVGEDAMKTPSP
  AAEDAREPEAKGNS
• Function: Scaffold protein that functions as a component of a multimolecular complex involved in histone mRNA 3'-end processing. Specific component of the tight junction (TJ) plaque, but might not be an exclusively junctional component. May have a house-keeping rule. Is involved in pre-mRNA polyadenylation. Enhances SSU72 phosphatase activity.
• Tissue Specificity: In testis, expressed in polar epithelia and Sertoli cells but not in vascular endothelia. The protein is detected in stomach, duodenum, pancreas, liver, fetal brain, carcinomas, lens-forming cells, fibroblasts, lymphocytes, lymphoma cells, erythroleukemia cells but not in endothelium of vessels, epidermis, intercalated disks, Purkinje fiber cells of the heart and lymph node.
• KEGG Pathway:
  mR. surveillance pathway (hsa03015)
  Tight junction (hsa04530)
• Reactome Pathway:
  mRNA 3'-end processing (R-HSA-72187)
  Processing of Capped Intron-Containing Pre-mRNA (R-HSA-72203)
  RNA Polymerase II Transcription Termination (R-HSA-73856)
  Processing of Intronless Pre-mRNAs (R-HSA-77595)
  Transport of Mature mRNA Derived from an Intronless Transcript (R-HSA-159231)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colon cancer	DISVC52G	Strong	Genetic Variation	[1]
Colon carcinoma	DISJYKUO	Strong	Genetic Variation	[1]
Colonic neoplasm	DISSZ04P	Strong	Genetic Variation	[1]
Colorectal adenocarcinoma	DISPQOUB	Strong	Genetic Variation	[1]
Colorectal cancer	DISNH7P9	Strong	Genetic Variation	[1]
Colorectal cancer, susceptibility to, 1	DISZ794C	Strong	Genetic Variation	[1]
Colorectal cancer, susceptibility to, 10	DISQXMYM	Strong	Genetic Variation	[1]
Colorectal cancer, susceptibility to, 12	DIS4FXJX	Strong	Genetic Variation	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[1]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[1]
Gastric cancer	DISXGOUK	Strong	Biomarker	[2]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[2]
Gastroparesis	DISDW0SR	Strong	Biomarker	[3]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[2]
Immunodeficiency	DIS093I0	Strong	Altered Expression	[4]
Leber congenital amaurosis 2	DISF39MM	Strong	Genetic Variation	[5]
Xerophthalmia	DIS5B72B	Strong	Biomarker	[6]
Dyspepsia	DISYEEY6	Disputed	Biomarker	[7]
Hepatitis	DISXXX35	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Symplekin (SYMPK).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Symplekin (SYMPK).	[17]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Symplekin (SYMPK).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Symplekin (SYMPK).	[20]

13 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin affects the expression of Symplekin (SYMPK).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Symplekin (SYMPK).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Symplekin (SYMPK).	[12]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Symplekin (SYMPK).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Symplekin (SYMPK).	[14]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Symplekin (SYMPK).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Symplekin (SYMPK).	[16]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Symplekin (SYMPK).	[10]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of Symplekin (SYMPK).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Symplekin (SYMPK).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Symplekin (SYMPK).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Symplekin (SYMPK).	[22]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Symplekin (SYMPK).	[23]

References

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• [3] Spatial Patterns From High-Resolution Electrogastrography Correlate With Severity of Symptoms in Patients With Functional Dyspepsia and Gastroparesis.Clin Gastroenterol Hepatol. 2019 Dec;17(13):2668-2677. doi: 10.1016/j.cgh.2019.04.039. Epub 2019 Apr 19.
• [4] Symplekin promotes tumorigenicity by up-regulating claudin-2 expression.Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2628-33. doi: 10.1073/pnas.0903747107. Epub 2010 Jan 25.
• [5] Investor Outlook: Significance of the Positive LCA2 Gene Therapy Phase III Results.Hum Gene Ther Clin Dev. 2015 Dec;26(4):208-10. doi: 10.1089/humc.2015.29004.sch.
• [6] The Effect of Ocular Surface Regularity on Contrast Sensitivity and Straylight in Dry Eye.Invest Ophthalmol Vis Sci. 2017 May 1;58(5):2647-2651. doi: 10.1167/iovs.17-21894.
• [7] Rikkunshito simultaneously improves dyspepsia correlated with anxiety in patients with functional dyspepsia: A randomized clinical trial (the DREAM study).Neurogastroenterol Motil. 2018 Jul;30(7):e13319. doi: 10.1111/nmo.13319. Epub 2018 Mar 2.
• [8] Telmisartan and/or chlorogenic acid attenuates fructose-induced non-alcoholic fatty liver disease in rats: Implications of cross-talk between angiotensin, the sphingosine kinase/sphingoine-1-phosphate pathway, and TLR4 receptors.Biochem Pharmacol. 2019 Jun;164:252-262. doi: 10.1016/j.bcp.2019.04.018. Epub 2019 Apr 18.
• [9] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [10] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [11] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [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] Identification of novel ER-alpha target genes in breast cancer cells: gene- and cell-selective co-regulator recruitment at target promoters determines the response to 17beta-estradiol and tamoxifen. Mol Cell Endocrinol. 2010 Jan 15;314(1):90-100.
• [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] Cellular response to 5-fluorouracil (5-FU) in 5-FU-resistant colon cancer cell lines during treatment and recovery. Mol Cancer. 2006 May 18;5:20. doi: 10.1186/1476-4598-5-20.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [19] 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.
• [20] 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.
• [21] Cultured human peripheral blood mononuclear cells alter their gene expression when challenged with endocrine-disrupting chemicals. Toxicology. 2013 Jan 7;303:17-24.
• [22] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [23] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.