Details of Drug Off-Target (DOT)

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

• DOT Name: Disks large-associated protein 4 (DLGAP4)
• Synonyms: DAP-4; PSD-95/SAP90-binding protein 4; SAP90/PSD-95-associated protein 4; SAPAP-4
• Gene Name: DLGAP4
• Related Disease:
  Advanced cancer
  Autism spectrum disorder
  Cerebellar ataxia
  Endometrial cancer
  Endometrial carcinoma
  Gastric cancer
  Parkinson disease
  Stomach cancer
  Methicillin-resistant staphylococci infection
  Staphylococcus infection
  Autism
  Neurodevelopmental disorder
• UniProt ID: DLGP4_HUMAN
• Pfam ID: PF03359
• Sequence:
  MKGLGDSRPRHLSDSLDPPHEPLFAGTDRNPYLLSPTEAFAREARFPGQNTLPGDGLFPL
  NNQLPPPSSTFPRIHYNSHFEVPEESPFPSHAQATKINRLPANLLDQFEKQLPIHRDGFS
  TLQFPRGEAKARGESPGRIRHLVHSVQRLFFTKAPSLEGTAGKVGGNGSKKGGMEDGKGR
  RAKSKERAKAGEPKRRSRSNISGWWSSDDNLDGEAGAFRSSGPASGLMTLGRQAERSQPR
  YFMHAYNTISGHMLKTTKNNTTELTAPPPPPAPPATCPSLGVGTDTNYVKRGSWSTLTLS
  HAHEVCQKTSATLDKSLLKSKSCHQGLAYHYLQVPGGGGEWSTTLLSPRETDAAAEGPIP
  CRRMRSGSYIKAMGDEDSDESGGSPKPSPKTAARRQSYLRATQQSLGEQSNPRRSLDRLD
  SVDMLLPSKCPSWEEDYTPVSDSLNDSSCISQIFGQASLIPQLFGHEQQVREAELSDQYE
  AACESACSEAESTAAETLDLPLPSYFRSRSHSYLRAIQAGCSQEEDSVSLQSLSPPPSTG
  SLSNSRTLPSSSCLVAYKKTPPPVPPRTTSKPFISVTVQSSTESAQDTYLDSQDHKSEVT
  SQSGLSNSSDSLDSSTRPPSVTRGGVAPAPEAPEPPPKHAALKSEQGTLTSSESHPEAAP
  KRKLSSIGIQVDCIQPVPKEEPSPATKFQSIGVQVEDDWRSSVPSHSMSSRRDTDSDTQD
  ANDSSCKSSERSLPDCTPHPNSISIDAGPRQAPKIAQIKRNLSYGDNSDPALEASSLPPP
  DPWLETSSSSPAEPAQPGACRRDGYWFLKLLQAETERLEGWCCQMDKETKENNLSEEVLG
  KVLSAVGSAQLLMSQKFQQFRGLCEQNLNPDANPRPTAQDLAGFWDLLQLSIEDISMKFD
  ELYHLKANSWQLVETPEKRKEEKKPPPPVPKKPAKSKPAVSRDKASDASDKQRQEARKRL
  LAAKRAASVRQNSATESADSIEIYVPEAQTRL
• Function: May play a role in the molecular organization of synapses and neuronal cell signaling. Could be an adapter protein linking ion channel to the subsynaptic cytoskeleton. May induce enrichment of PSD-95/SAP90 at the plasma membrane.
• Reactome Pathway: Neurexins and neuroligins (R-HSA-6794361)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[2]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[3]
Endometrial cancer	DISW0LMR	Strong	Genetic Variation	[4]
Endometrial carcinoma	DISXR5CY	Strong	Genetic Variation	[4]
Gastric cancer	DISXGOUK	Strong	Biomarker	[1]
Parkinson disease	DISQVHKL	Strong	Altered Expression	[5]
Stomach cancer	DISKIJSX	Strong	Biomarker	[1]
Methicillin-resistant staphylococci infection	DIS6DRDZ	moderate	Biomarker	[6]
Staphylococcus infection	DISY8WGS	moderate	Biomarker	[6]
Autism	DISV4V1Z	Limited	Biomarker	[2]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Disks large-associated protein 4 (DLGAP4).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Disks large-associated protein 4 (DLGAP4).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Disks large-associated protein 4 (DLGAP4).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Disks large-associated protein 4 (DLGAP4).	[10]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Disks large-associated protein 4 (DLGAP4).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Disks large-associated protein 4 (DLGAP4).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Disks large-associated protein 4 (DLGAP4).	[14]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Disks large-associated protein 4 (DLGAP4).	[15]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Disks large-associated protein 4 (DLGAP4).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Disks large-associated protein 4 (DLGAP4).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Disks large-associated protein 4 (DLGAP4).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Disks large-associated protein 4 (DLGAP4).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Disks large-associated protein 4 (DLGAP4).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Disks large-associated protein 4 (DLGAP4).	[23]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of Disks large-associated protein 4 (DLGAP4).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Disks large-associated protein 4 (DLGAP4).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Disks large-associated protein 4 (DLGAP4).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Disks large-associated protein 4 (DLGAP4).	[21]

References

• [1] Examination of the expression and prognostic significance of DLGAPs in gastric cancer using the TCGA database and bioinformatic analysis.Mol Med Rep. 2018 Dec;18(6):5621-5629. doi: 10.3892/mmr.2018.9574. Epub 2018 Oct 23.
• [2] Cognitive impairment and autistic-like behaviour in SAPAP4-deficient mice.Transl Psychiatry. 2019 Jan 16;9(1):7. doi: 10.1038/s41398-018-0327-z.
• [3] Epigenetic remodelling and dysregulation of DLGAP4 is linked with early-onset cerebellar ataxia.Hum Mol Genet. 2014 Dec 1;23(23):6163-76. doi: 10.1093/hmg/ddu337. Epub 2014 Jul 1.
• [4] Exome-Wide Rare Variant Analysis From the DiscovEHR Study Identifies Novel Candidate Predisposition Genes for Endometrial Cancer.Front Oncol. 2019 Jul 5;9:574. doi: 10.3389/fonc.2019.00574. eCollection 2019.
• [5] Circular RNA circDLGAP4 exerts neuroprotective effects via modulating miR-134-5p/CREB pathway in Parkinson's disease.Biochem Biophys Res Commun. 2020 Feb 5;522(2):388-394. doi: 10.1016/j.bbrc.2019.11.102. Epub 2019 Nov 21.
• [6] Antibacterial and immunomodulatory activities of insect defensins-DLP2 and DLP4 against multidrug-resistant Staphylococcus aureus.Sci Rep. 2017 Sep 21;7(1):12124. doi: 10.1038/s41598-017-10839-4.
• [7] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [12] 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.
• [13] 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.
• [14] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [15] 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.
• [16] 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.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] 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.
• [19] 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.
• [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] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [24] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.