Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH591WK)

• DOT Name: Disks large homolog 3 (DLG3)
• Synonyms: Neuroendocrine-DLG; Synapse-associated protein 102; SAP-102; SAP102; XLMR
• Gene Name: DLG3
• Related Disease:
  Intellectual disability, X-linked 90
  Non-syndromic X-linked intellectual disability
  Advanced cancer
  Alzheimer disease
  Bipolar disorder
  Breast cancer
  Breast carcinoma
  Fragile X syndrome
  Intellectual disability, X-linked 1
  Intellectual disability, X-linked 100
  Intellectual disability, X-linked 19
  Intellectual disability, X-linked 30
  Intellectual disability, X-linked 41
  Intellectual disability, X-linked 45
  Intellectual disability, X-linked 46
  Intellectual disability, X-linked 49
  Intellectual disability, X-linked 58
  Intellectual disability, X-linked 63
  Intellectual disability, X-linked 72
  Intellectual disability, X-linked 9
  Intellectual disability, X-linked 91
  Intellectual disability, X-linked 93
  Intellectual disability, X-linked 95
  Intellectual disability, X-linked 96
  Intellectual disability, X-linked 97
  Intellectual disability, X-linked 99
  Major depressive disorder
  Mood disorder
  Nervous system disease
  Non-small-cell lung cancer
  X-linked intellectual disability
  X-linked intellectual disability, Cantagrel type
  Movement disorder
  Neoplasm
• UniProt ID: DLG3_HUMAN
• PDB ID: 1UM7; 2FE5; 2I1N
• Pfam ID: PF00625 ; PF00595 ; PF10600 ; PF00018
• Sequence:
  MHKHQHCCKCPECYEVTRLAALRRLEPPGYGDWQVPDPYGPGGGNGASAGYGGYSSQTLP
  SQAGATPTPRTKAKLIPTGRDVGPVPPKPVPGKSTPKLNGSGPSWWPECTCTNRDWYEQV
  NGSDGMFKYEEIVLERGNSGLGFSIAGGIDNPHVPDDPGIFITKIIPGGAAAMDGRLGVN
  DCVLRVNEVDVSEVVHSRAVEALKEAGPVVRLVVRRRQPPPETIMEVNLLKGPKGLGFSI
  AGGIGNQHIPGDNSIYITKIIEGGAAQKDGRLQIGDRLLAVNNTNLQDVRHEEAVASLKN
  TSDMVYLKVAKPGSLHLNDMYAPPDYASTFTALADNHISHNSSLGYLGAVESKVSYPAPP
  QVPPTRYSPIPRHMLAEEDFTREPRKIILHKGSTGLGFNIVGGEDGEGIFVSFILAGGPA
  DLSGELRRGDRILSVNGVNLRNATHEQAAAALKRAGQSVTIVAQYRPEEYSRFESKIHDL
  REQMMNSSMSSGSGSLRTSEKRSLYVRALFDYDRTRDSCLPSQGLSFSYGDILHVINASD
  DEWWQARLVTPHGESEQIGVIPSKKRVEKKERARLKTVKFHARTGMIESNRDFPGLSDDY
  YGAKNLKGQEDAILSYEPVTRQEIHYARPVIILGPMKDRVNDDLISEFPHKFGSCVPHTT
  RPRRDNEVDGQDYHFVVSREQMEKDIQDNKFIEAGQFNDNLYGTSIQSVRAVAERGKHCI
  LDVSGNAIKRLQQAQLYPIAIFIKPKSIEALMEMNRRQTYEQANKIYDKAMKLEQEFGEY
  FTAIVQGDSLEEIYNKIKQIIEDQSGHYIWVPSPEKL
• Function: Required for learning most likely through its role in synaptic plasticity following NMDA receptor signaling.
• KEGG Pathway:
  Hippo sig.ling pathway (hsa04390)
  Tight junction (hsa04530)
  Human papillomavirus infection (hsa05165)
• Reactome Pathway:
  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)
  Neurexins and neuroligins (R-HSA-6794361)
  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)
  Unblocking of NMDA receptors, glutamate binding and activation (R-HSA-438066)

Molecular Interaction Atlas (MIA) of This DOT

34 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability, X-linked 90	DISLGNWQ	Definitive	X-linked recessive	[1]
Non-syndromic X-linked intellectual disability	DIS71AI3	Definitive	X-linked	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
Bipolar disorder	DISAM7J2	Strong	Altered Expression	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Fragile X syndrome	DISE8W3A	Strong	Genetic Variation	[7]
Intellectual disability, X-linked 1	DISET38E	Strong	Biomarker	[8]
Intellectual disability, X-linked 100	DISX6CQ7	Strong	Biomarker	[8]
Intellectual disability, X-linked 19	DIS240KZ	Strong	Biomarker	[8]
Intellectual disability, X-linked 30	DISOEQO6	Strong	Biomarker	[8]
Intellectual disability, X-linked 41	DISMG202	Strong	Biomarker	[8]
Intellectual disability, X-linked 45	DIS1TLM2	Strong	Biomarker	[8]
Intellectual disability, X-linked 46	DISO2WQ2	Strong	Biomarker	[8]
Intellectual disability, X-linked 49	DISKDVXD	Strong	Biomarker	[8]
Intellectual disability, X-linked 58	DISRMLYX	Strong	Biomarker	[8]
Intellectual disability, X-linked 63	DISEBC1L	Strong	Biomarker	[8]
Intellectual disability, X-linked 72	DISQC206	Strong	Biomarker	[8]
Intellectual disability, X-linked 9	DISWT4BP	Strong	Biomarker	[8]
Intellectual disability, X-linked 91	DISVSHJD	Strong	Biomarker	[8]
Intellectual disability, X-linked 93	DIS5EFCO	Strong	Biomarker	[8]
Intellectual disability, X-linked 95	DIS1QZO7	Strong	Biomarker	[8]
Intellectual disability, X-linked 96	DIS14ZZ5	Strong	Biomarker	[8]
Intellectual disability, X-linked 97	DISQINN0	Strong	Biomarker	[8]
Intellectual disability, X-linked 99	DISW92UF	Strong	Biomarker	[8]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[5]
Mood disorder	DISLVMWO	Strong	Biomarker	[9]
Nervous system disease	DISJ7GGT	Strong	Biomarker	[10]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[11]
X-linked intellectual disability	DISYJBY3	Strong	Biomarker	[12]
X-linked intellectual disability, Cantagrel type	DISP424V	Strong	Biomarker	[8]
Movement disorder	DISOJJ2D	moderate	CausalMutation	[13]
Neoplasm	DISZKGEW	Limited	Biomarker	[14]

3 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 Disks large homolog 3 (DLG3).	[15]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Disks large homolog 3 (DLG3).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Disks large homolog 3 (DLG3).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Disks large homolog 3 (DLG3).	[16]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Disks large homolog 3 (DLG3).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Disks large homolog 3 (DLG3).	[18]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Disks large homolog 3 (DLG3).	[20]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Disks large homolog 3 (DLG3).	[21]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Disks large homolog 3 (DLG3).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Disks large homolog 3 (DLG3).	[24]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Disks large homolog 3 (DLG3).	[25]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Disks large homolog 3 (DLG3).	[26]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] SAP102 contributes to hyperalgesia formation in the cancer induced bone pain rat model by anchoring NMDA receptors.Neurosci Lett. 2020 Jan 1;714:134595. doi: 10.1016/j.neulet.2019.134595. Epub 2019 Nov 1.
• [4] Dynamic SAP102 expression in the hippocampal subregions of rats and APP/PS1 mice of various ages.J Anat. 2018 Jun;232(6):987-996. doi: 10.1111/joa.12807. Epub 2018 Mar 25.
• [5] Lamina-specific abnormalities of NMDA receptor-associated postsynaptic protein transcripts in the prefrontal cortex in schizophrenia and bipolar disorder.Neuropsychopharmacology. 2008 Aug;33(9):2175-86. doi: 10.1038/sj.npp.1301604. Epub 2007 Nov 21.
• [6] High expression of DLG3 is associated with decreased survival from breast cancer.Clin Exp Pharmacol Physiol. 2019 Oct;46(10):937-943. doi: 10.1111/1440-1681.13132. Epub 2019 Jul 31.
• [7] Central nervous system neoplasm in a young man with Martin-Bell syndrome--fra(X)-XLMR.Am J Med Genet. 1987 Jan;26(1):7-12. doi: 10.1002/ajmg.1320260103.
• [8] Altered thalamocortical development in the SAP102 knockout model of intellectual disability.Hum Mol Genet. 2016 Sep 15;25(18):4052-4061. doi: 10.1093/hmg/ddw244. Epub 2016 Jul 27.
• [9] Abnormal striatal expression of transcripts encoding NMDA interacting PSD proteins in schizophrenia, bipolar disorder and major depression.Schizophr Res. 2005 Oct 1;78(1):87-93. doi: 10.1016/j.schres.2005.06.012.
• [10] Submicroscopic duplications of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental retardation. Am J Hum Genet. 2008 Feb;82(2):432-43. doi: 10.1016/j.ajhg.2007.11.002. Epub 2008 Jan 24.
• [11] MERTK Promotes Resistance to Irreversible EGFR Tyrosine Kinase Inhibitors in Non-small Cell Lung Cancers Expressing Wild-type EGFR Family Members.Clin Cancer Res. 2018 Dec 15;24(24):6523-6535. doi: 10.1158/1078-0432.CCR-18-0040. Epub 2018 Sep 7.
• [12] Fine mapping of Xq11.1-q21.33 and mutation screening of RPS6KA6, ZNF711, ACSL4, DLG3, and IL1RAPL2 for autism spectrum disorders (ASD).Autism Res. 2011 Jun;4(3):228-33. doi: 10.1002/aur.187. Epub 2011 Feb 22.
• [13] Skewed X-inactivation in a family with DLG3-associated X-linked intellectual disability.Am J Med Genet A. 2017 Sep;173(9):2545-2550. doi: 10.1002/ajmg.a.38348. Epub 2017 Aug 4.
• [14] Profiling of differentially expressed genes in human gastric carcinoma by cDNA expression array.World J Gastroenterol. 2002 Aug;8(4):580-5. doi: 10.3748/wjg.v8.i4.580.
• [15] 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.
• [16] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [17] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [18] 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.
• [19] 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.
• [20] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [26] 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.