Details of Drug Off-Target (DOT)

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

• DOT Name: Synaptopodin (SYNPO)
• Gene Name: SYNPO
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Bone cancer
  Bone osteosarcoma
  Epilepsy
  Focal segmental glomerulosclerosis
  IgA nephropathy
  Lupus
  Membranous glomerulonephritis
  Nephropathy
  Nephrotic syndrome
  Pre-eclampsia
  Prostate cancer
  Schizophrenia
  Status epilepticus seizure
  Systemic lupus erythematosus
  Breast cancer
  Breast carcinoma
  Fatty liver disease
  Obesity
  Wilms tumor
  Eosinophilic esophagitis
  Fabry disease
  Lewy body dementia
• UniProt ID: SYNPO_HUMAN
• Sequence:
  MLGPHLPPPPLAPSEGRPTPCAFQIPDGSYRCLALEAEESSGEEGLQGEVGPTDLEEDEG
  VSRSGDDSACRVTQGTPQLPKALGIQPPSCSREEQGASQHDDRASQDWDVVKAGQMMTAS
  PSPGPGPRVAQKPALGRSTSLTEKDLKEAKARSQQIAAQLTTPPSSNSRGVQLFNRRRQR
  VNEFTLESHGQRGQKPSQESLRVLPSSLPGHAPGLSLSSTSLPEPGPPRHPSPQSPDRGV
  PGHSMEGYSEEASLLRHLEKVASEEEEVPLVVYLKENAALLTANGLHLSQNREAQQSSPA
  PPPAEVHSPAADVNQNLASPSATLTTPTSNSSHNPPATDVNQNPPATVVPQSLPLSSIQQ
  NSSEAQLPSNGTGPASKPSTLCADGQPQAPAEEVRCSTLLIDKVSTPATTTSTFSREATL
  IPSSRPPASDFMSSSLLIDIQPNTLVVSADQEMSGRAAATTPTKVYSEVHFTLAKPPSVV
  NRTARPFGIQAPGGTSQMERSPMLERRHFGEKAPAPQPPSLPDRSPRPQRHIMSRSPMVE
  RRMMGQRSPASERRPLGNFTAPPTYTETLSTAPLASWVRSPPSYSVLYPSSDPKSSHLKG
  QAVPASKTGILEESMARRGSRKSMFTFVEKPKVTPNPDLLDLVQTADEKRRQRDQGEVGV
  EEEPFALGAEASNFQQEPAPRDRASPAAAEEVVPEWASCLKSPRIQAKPKPKPNQNLSEA
  SGKGAELYARRQSRMEKYVIESSSHTPELARCPSPTMSLPSSWKYPTNAPGAFRVASRSP
  ARTPPASLYHGYLPENGVLRPEPTKQPPYQLRPSLFVLSPIKEPAKVSPRAASPAKPSSL
  DLVPNLPKGALPPSPALPRPSRSSPGLYTSPGQDSLQPTAVSPPYGGDISPVSPSRAWSP
  RAKQAPRPSFSTRNAGIEAQVWKPSFCFK
• Function: Actin-associated protein that may play a role in modulating actin-based shape and motility of dendritic spines and renal podocyte foot processes. Seems to be essential for the formation of spine apparatuses in spines of telencephalic neurons, which is involved in synaptic plasticity.
• Tissue Specificity: Expressed in cerebral cortex.
• KEGG Pathway: Tight junction (hsa04530)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Bone cancer	DIS38NA0	Strong	Biomarker	[1]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[1]
Epilepsy	DISBB28L	Strong	Biomarker	[3]
Focal segmental glomerulosclerosis	DISJNHH0	Strong	Altered Expression	[4]
IgA nephropathy	DISZ8MTK	Strong	Altered Expression	[5]
Lupus	DISOKJWA	Strong	Biomarker	[6]
Membranous glomerulonephritis	DISFSUKQ	Strong	Altered Expression	[7]
Nephropathy	DISXWP4P	Strong	Biomarker	[8]
Nephrotic syndrome	DISSPSC2	Strong	Biomarker	[9]
Pre-eclampsia	DISY7Q29	Strong	Altered Expression	[10]
Prostate cancer	DISF190Y	Strong	Biomarker	[11]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[12]
Status epilepticus seizure	DISY3BIC	Strong	Biomarker	[3]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	moderate	Biomarker	[13]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[13]
Fatty liver disease	DIS485QZ	moderate	Altered Expression	[14]
Obesity	DIS47Y1K	moderate	Biomarker	[14]
Wilms tumor	DISB6T16	Disputed	Altered Expression	[15]
Eosinophilic esophagitis	DISR8WSB	Limited	Biomarker	[16]
Fabry disease	DISUUQJF	Limited	Altered Expression	[17]
Lewy body dementia	DISAE66J	Limited	Altered Expression	[18]

12 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 Synaptopodin (SYNPO).	[19]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Synaptopodin (SYNPO).	[21]
Marinol	DM70IK5	Approved	Marinol increases the expression of Synaptopodin (SYNPO).	[23]
Selenium	DM25CGV	Approved	Selenium increases the expression of Synaptopodin (SYNPO).	[24]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Synaptopodin (SYNPO).	[25]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Synaptopodin (SYNPO).	[26]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Synaptopodin (SYNPO).	[27]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Synaptopodin (SYNPO).	[28]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Synaptopodin (SYNPO).	[24]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Synaptopodin (SYNPO).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Synaptopodin (SYNPO).	[32]
Cycloheximide	DMGDA3C	Investigative	Cycloheximide increases the expression of Synaptopodin (SYNPO).	[34]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Synaptopodin (SYNPO).	[20]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Synaptopodin (SYNPO).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Synaptopodin (SYNPO).	[29]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Synaptopodin (SYNPO).	[31]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Synaptopodin (SYNPO).	[31]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the methylation of Synaptopodin (SYNPO).	[33]

References

• [1] Spinal miRNA-124 regulates synaptopodin and nociception in an animal model of bone cancer pain.Sci Rep. 2017 Sep 8;7(1):10949. doi: 10.1038/s41598-017-10224-1.
• [2] Synaptopodin Deficiency Ameliorates Symptoms in the 3xTg Mouse Model of Alzheimer's Disease.J Neurosci. 2019 May 15;39(20):3983-3992. doi: 10.1523/JNEUROSCI.2920-18.2019. Epub 2019 Mar 14.
• [3] Pilocarpine-Induced Status Epilepticus Is Associated with Changes in the Actin-Modulating Protein Synaptopodin and Alterations in Long-Term Potentiation in the Mouse Hippocampus.Neural Plast. 2017;2017:2652560. doi: 10.1155/2017/2652560. Epub 2017 Jan 5.
• [4] Urinary myo-inositol is associated with the clinical outcome in focal segmental glomerulosclerosis.Sci Rep. 2019 Oct 11;9(1):14707. doi: 10.1038/s41598-019-51276-9.
• [5] Podocyte injury induced by mesangial-derived cytokines in IgA nephropathy.Nephrol Dial Transplant. 2009 Jan;24(1):62-72. doi: 10.1093/ndt/gfn441. Epub 2008 Aug 6.
• [6] Mesenchymal stem cells prevent podocyte injury in lupus-prone B6.MRL-Faslpr mice via polarizing macrophage into an anti-inflammatory phenotype.Nephrol Dial Transplant. 2019 Apr 1;34(4):597-605. doi: 10.1093/ndt/gfy195.
• [7] Alteration of histone H3K4 methylation in glomerular podocytes associated with proteinuria in patients with membranous nephropathy.BMC Nephrol. 2016 Nov 17;17(1):179. doi: 10.1186/s12882-016-0390-8.
• [8] Proteinuric Kidney Diseases: A Podocyte's Slit Diaphragm and Cytoskeleton Approach.Front Med (Lausanne). 2018 Sep 11;5:221. doi: 10.3389/fmed.2018.00221. eCollection 2018.
• [9] Synaptopodin protects against proteinuria by disrupting Cdc42:IRSp53:Mena signaling complexes in kidney podocytes.Am J Pathol. 2007 Aug;171(2):415-27. doi: 10.2353/ajpath.2007.070075. Epub 2007 Jun 14.
• [10] Glomerular expression of nephrin and synaptopodin, but not podocin, is decreased in kidney sections from women with preeclampsia.Nephrol Dial Transplant. 2007 Apr;22(4):1136-43. doi: 10.1093/ndt/gfl711. Epub 2007 Jan 25.
• [11] Myopodin, a synaptopodin homologue, is frequently deleted in invasive prostate cancers.Am J Pathol. 2001 Nov;159(5):1603-12. doi: 10.1016/S0002-9440(10)63006-4.
• [12] Exome Sequence Data From Multigenerational Families Implicate AMPA Receptor Trafficking in Neurocognitive Impairment and Schizophrenia Risk.Schizophr Bull. 2016 Mar;42(2):288-300. doi: 10.1093/schbul/sbv135. Epub 2015 Sep 24.
• [13] Rescue of tropomyosin deficiency in Drosophila and human cancer cells by synaptopodin reveals a role of tropomyosin in RhoA stabilization.EMBO J. 2012 Feb 15;31(4):1028-40. doi: 10.1038/emboj.2011.464. Epub 2011 Dec 13.
• [14] Elafibranor Inhibits Chronic Kidney Disease Progression in NASH Mice.Biomed Res Int. 2019 Jun 19;2019:6740616. doi: 10.1155/2019/6740616. eCollection 2019.
• [15] Knockdown of TLR4 attenuates high glucose-induced podocyte injury via the NALP3/ASC/Caspase-1 signaling pathway.Biomed Pharmacother. 2018 Nov;107:1393-1401. doi: 10.1016/j.biopha.2018.08.134. Epub 2018 Aug 31.
• [16] Synaptopodin is upregulated by IL-13 in eosinophilic esophagitis and regulates esophageal epithelial cell motility and barrier integrity.JCI Insight. 2017 Oct 19;2(20):e96789. doi: 10.1172/jci.insight.96789.
• [17] A heterozygous female with Fabry disease due to a novel -galactosidase A mutation exhibits a unique synaptopodin distribution in vacuolated podocytes.Clin Nephrol. 2015 May;83(5):301-8. doi: 10.5414/CN108317.
• [18] An iTRAQ-based proteomic analysis reveals dysregulation of neocortical synaptopodin in Lewy body dementias.Mol Brain. 2017 Aug 11;10(1):36. doi: 10.1186/s13041-017-0316-9.
• [19] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [20] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [21] 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.
• [22] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [23] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [24] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [25] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [26] Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
• [27] 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.
• [28] Genistein disrupts glucocorticoid receptor signaling in human uterine endometrial Ishikawa cells. Environ Health Perspect. 2015 Jan;123(1):80-7. doi: 10.1289/ehp.1408437. Epub 2014 Aug 19.
• [29] 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.
• [30] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [31] 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.
• [32] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [33] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [34] Comparative analysis of AhR-mediated TCDD-elicited gene expression in human liver adult stem cells. Toxicol Sci. 2009 Nov;112(1):229-44.