Details of Drug Off-Target (DOT)

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

• DOT Name: Disks large homolog 1 (DLG1)
• Synonyms: Synapse-associated protein 97; SAP-97; SAP97; hDlg
• Gene Name: DLG1
• Related Disease:
  Hyperglycemia
  Adult T-cell leukemia/lymphoma
  Advanced cancer
  Alzheimer disease
  Colonic neoplasm
  Crohn disease
  Dilated cardiomyopathy 1A
  Huntington disease
  Isolated cleft palate
  Kidney failure
  Parkinson disease
  Uterine cervix neoplasm
  Esophageal squamous cell carcinoma
  Bladder cancer
  Brugada syndrome
  Cleft lip/palate
  Neoplasm
  Urinary bladder cancer
  Urinary bladder neoplasm
• UniProt ID: DLG1_HUMAN
• PDB ID: 1PDR; 2M3M; 2OQS; 2X7Z; 3LRA; 3RL7; 3RL8; 3W9Y; 4AMH; 4G69; 7PC3; 8CN1; 8CN3
• Pfam ID: PF00625 ; PF09058 ; PF10608 ; PF00595 ; PF10600 ; PF00018
• Sequence:
  MPVRKQDTQRALHLLEEYRSKLSQTEDRQLRSSIERVINIFQSNLFQALIDIQEFYEVTL
  LDNPKCIDRSKPSEPIQPVNTWEISSLPSSTVTSETLPSSLSPSVEKYRYQDEDTPPQEH
  ISPQITNEVIGPELVHVSEKNLSEIENVHGFVSHSHISPIKPTEAVLPSPPTVPVIPVLP
  VPAENTVILPTIPQANPPPVLVNTDSLETPTYVNGTDADYEYEEITLERGNSGLGFSIAG
  GTDNPHIGDDSSIFITKIITGGAAAQDGRLRVNDCILRVNEVDVRDVTHSKAVEALKEAG
  SIVRLYVKRRKPVSEKIMEIKLIKGPKGLGFSIAGGVGNQHIPGDNSIYVTKIIEGGAAH
  KDGKLQIGDKLLAVNNVCLEEVTHEEAVTALKNTSDFVYLKVAKPTSMYMNDGYAPPDIT
  NSSSQPVDNHVSPSSFLGQTPASPARYSPVSKAVLGDDEITREPRKVVLHRGSTGLGFNI
  VGGEDGEGIFISFILAGGPADLSGELRKGDRIISVNSVDLRAASHEQAAAALKNAGQAVT
  IVAQYRPEEYSRFEAKIHDLREQMMNSSISSGSGSLRTSQKRSLYVRALFDYDKTKDSGL
  PSQGLNFKFGDILHVINASDDEWWQARQVTPDGESDEVGVIPSKRRVEKKERARLKTVKF
  NSKTRDKGEIPDDMGSKGLKHVTSNASDSESSYRGQEEYVLSYEPVNQQEVNYTRPVIIL
  GPMKDRINDDLISEFPDKFGSCVPHTTRPKRDYEVDGRDYHFVTSREQMEKDIQEHKFIE
  AGQYNNHLYGTSVQSVREVAEKGKHCILDVSGNAIKRLQIAQLYPISIFIKPKSMENIME
  MNKRLTEEQARKTFERAMKLEQEFTEHFTAIVQGDTLEDIYNQVKQIIEEQSGSYIWVPA
  KEKL
• Function: Essential multidomain scaffolding protein required for normal development. Recruits channels, receptors and signaling molecules to discrete plasma membrane domains in polarized cells. May play a role in adherens junction assembly, signal transduction, cell proliferation, synaptogenesis and lymphocyte activation. Regulates the excitability of cardiac myocytes by modulating the functional expression of Kv4 channels. Functional regulator of Kv1.5 channel. During long-term depression in hippocampal neurons, it recruits ADAM10 to the plasma membrane.
• Tissue Specificity: Abundantly expressed in atrial myocardium (at protein level). Expressed in lung fibroblasts, cervical epithelial and B-cells (at protein level). Expressed in the brain (at protein level) . Widely expressed, with isoforms displaying different expression profiles.
• KEGG Pathway:
  Hippo sig.ling pathway (hsa04390)
  Tight junction (hsa04530)
  T cell receptor sig.ling pathway (hsa04660)
  Human papillomavirus infection (hsa05165)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Viral carcinogenesis (hsa05203)
• Reactome Pathway:
  Unblocking of NMDA receptors, glutamate binding and activation (R-HSA-438066)
  Ras activation upon Ca2+ influx through NMDA receptor (R-HSA-442982)
  NrCAM interactions (R-HSA-447038)
  Activation of Ca-permeable Kainate Receptor (R-HSA-451308)
  RAF/MAP kinase cascade (R-HSA-5673001)
  Synaptic adhesion-like molecules (R-HSA-8849932)
  Assembly and cell surface presentation of NMDA receptors (R-HSA-9609736)
  Negative regulation of NMDA receptor-mediated neuronal transmission (R-HSA-9617324)
  Long-term potentiation (R-HSA-9620244)
  Trafficking of AMPA receptors (R-HSA-399719)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hyperglycemia	DIS0BZB5	Definitive	Altered Expression	[1]
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[5]
Crohn disease	DIS2C5Q8	Strong	Genetic Variation	[6]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Biomarker	[7]
Huntington disease	DISQPLA4	Strong	Biomarker	[8]
Isolated cleft palate	DISV80CD	Strong	Biomarker	[9]
Kidney failure	DISOVQ9P	Strong	Biomarker	[10]
Parkinson disease	DISQVHKL	Strong	Biomarker	[11]
Uterine cervix neoplasm	DIS0BYVV	Strong	Altered Expression	[12]
Esophageal squamous cell carcinoma	DIS5N2GV	moderate	Biomarker	[13]
Bladder cancer	DISUHNM0	Limited	Genetic Variation	[13]
Brugada syndrome	DISSGN0E	Limited	Unknown	[14]
Cleft lip/palate	DIS14IG3	Limited	SusceptibilityMutation	[15]
Neoplasm	DISZKGEW	Limited	Biomarker	[3]
Urinary bladder cancer	DISDV4T7	Limited	Genetic Variation	[13]
Urinary bladder neoplasm	DIS7HACE	Limited	Genetic Variation	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Disks large homolog 1 (DLG1).	[16]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Disks large homolog 1 (DLG1).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Disks large homolog 1 (DLG1).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Disks large homolog 1 (DLG1).	[19]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Disks large homolog 1 (DLG1).	[20]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Disks large homolog 1 (DLG1).	[21]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Disks large homolog 1 (DLG1).	[22]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Disks large homolog 1 (DLG1).	[23]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Disks large homolog 1 (DLG1).	[24]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Disks large homolog 1 (DLG1).	[25]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Disks large homolog 1 (DLG1).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Disks large homolog 1 (DLG1).	[27]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Disks large homolog 1 (DLG1).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Disks large homolog 1 (DLG1).	[30]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Disks large homolog 1 (DLG1).	[31]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Disks large homolog 1 (DLG1).	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Disks large homolog 1 (DLG1).	[28]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Disks large homolog 1 (DLG1).	[28]

References

• [1] O-GlcNAcylation of cardiac Nav1.5 contributes to the development of arrhythmias in diabetic hearts.Int J Cardiol. 2018 Jun 1;260:74-81. doi: 10.1016/j.ijcard.2018.02.099. Epub 2018 Feb 27.
• [2] Inactivation of tumor suppressor Dlg1 augments transformation of a T-cell line induced by human T-cell leukemia virus type 1 Tax protein.Retrovirology. 2006 Oct 17;3:71. doi: 10.1186/1742-4690-3-71.
• [3] Differential expression of DLG1 as a common trait in different human diseases: an encouraging issue in molecular pathology.Biol Chem. 2019 May 27;400(6):699-710. doi: 10.1515/hsz-2018-0350.
• [4] Phenotypic down-regulation of glutamate receptor subunit GluR1 in Alzheimer's disease.Neurobiol Aging. 1999 May-Jun;20(3):287-95. doi: 10.1016/s0197-4580(99)00035-4.
• [5] Human discs large and scrib are localized at the same regions in colon mucosa and changes in their expression patterns are correlated with loss of tissue architecture during malignant progression.Int J Cancer. 2006 Sep 15;119(6):1285-90. doi: 10.1002/ijc.21982.
• [6] Exome sequencing identifies DLG1 as a novel gene for potential susceptibility to Crohn's disease in a Chinese family study.PLoS One. 2014 Jun 17;9(6):e99807. doi: 10.1371/journal.pone.0099807. eCollection 2014.
• [7] Altered expression of genes for Kir ion channels in dilated cardiomyopathy.Can J Physiol Pharmacol. 2013 Aug;91(8):648-56. doi: 10.1139/cjpp-2012-0413. Epub 2013 Mar 4.
• [8] SAP97-mediated rescue of NMDA receptor surface distribution in a neuronal model of Huntington's disease.Hippocampus. 2018 Oct;28(10):707-723. doi: 10.1002/hipo.22995.
• [9] Craniofacial dysmorphogenesis including cleft palate in mice with an insertional mutation in the discs large gene.Mol Cell Biol. 2001 Mar;21(5):1475-83. doi: 10.1128/MCB.21.5.1475-1483.2001.
• [10] Discs-large homolog 1 regulates smooth muscle orientation in the mouse ureter.Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19872-7. doi: 10.1073/pnas.0609326103. Epub 2006 Dec 15.
• [11] Subcellular redistribution of the synapse-associated proteins PSD-95 and SAP97 in animal models of Parkinson's disease and L-DOPA-induced dyskinesia.FASEB J. 2005 Apr;19(6):583-5. doi: 10.1096/fj.04-1854fje. Epub 2005 Feb 9.
• [12] Differential expression of the human homologue of drosophila discs large oncosuppressor in histologic samples from human papillomavirus-associated lesions as a marker for progression to malignancy.Int J Cancer. 2004 Sep 1;111(3):373-80. doi: 10.1002/ijc.20275.
• [13] The biogenesis and biological functions of circular RNAs and their molecular diagnostic values in cancers.J Clin Lab Anal. 2020 Jan;34(1):e23049. doi: 10.1002/jcla.23049. Epub 2019 Sep 25.
• [14] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [15] Common variants in DLG1 locus are associated with non-syndromic cleft lip with or without cleft palate.Clin Genet. 2018 Apr;93(4):784-793. doi: 10.1111/cge.13141. Epub 2018 Feb 11.
• [16] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [17] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [18] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [19] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [20] 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.
• [21] 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.
• [22] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [23] 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.
• [24] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [25] 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.
• [26] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [27] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [28] 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.
• [29] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [30] 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.
• [31] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [32] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.