Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8YF3S5)

• DOT Name: Intersectin-1 (ITSN1)
• Synonyms: SH3 domain-containing protein 1A; SH3P17
• Gene Name: ITSN1
• Related Disease:
  Coronary heart disease
  Rheumatoid arthritis
  Alzheimer disease
  Androgen insensitivity syndrome
  Arterial disorder
  Glioma
  Lung cancer
  Lung carcinoma
  Prostate cancer
  Prostate neoplasm
  Pulmonary disease
  Adult glioblastoma
  Breast cancer
  Breast carcinoma
  Glioblastoma multiforme
  Intellectual disability
  Isolated congenital microcephaly
  Neoplasm
  Neuroblastoma
  Pulmonary arterial hypertension
• UniProt ID: ITSN1_HUMAN
• PDB ID: 1KI1; 2KGR; 2KHN; 3FIA; 3QBV; 4IIM; 5HZI; 5HZJ; 5HZK; 6GBU; 6H5T
• Pfam ID: PF00168 ; PF12763 ; PF16617 ; PF16652 ; PF00621 ; PF00018 ; PF07653 ; PF14604
• Sequence:
  MAQFPTPFGGSLDIWAITVEERAKHDQQFHSLKPISGFITGDQARNFFFQSGLPQPVLAQ
  IWALADMNNDGRMDQVEFSIAMKLIKLKLQGYQLPSALPPVMKQQPVAISSAPAFGMGGI
  ASMPPLTAVAPVPMGSIPVVGMSPTLVSSVPTAAVPPLANGAPPVIQPLPAFAHPAATLP
  KSSSFSRSGPGSQLNTKLQKAQSFDVASVPPVAEWAVPQSSRLKYRQLFNSHDKTMSGHL
  TGPQARTILMQSSLPQAQLASIWNLSDIDQDGKLTAEEFILAMHLIDVAMSGQPLPPVLP
  PEYIPPSFRRVRSGSGISVISSTSVDQRLPEEPVLEDEQQQLEKKLPVTFEDKKRENFER
  GNLELEKRRQALLEQQRKEQERLAQLERAEQERKERERQEQERKRQLELEKQLEKQRELE
  RQREEERRKEIERREAAKRELERQRQLEWERNRRQELLNQRNKEQEDIVVLKAKKKTLEF
  ELEALNDKKHQLEGKLQDIRCRLTTQRQEIESTNKSRELRIAEITHLQQQLQESQQMLGR
  LIPEKQILNDQLKQVQQNSLHRDSLVTLKRALEAKELARQHLRDQLDEVEKETRSKLQEI
  DIFNNQLKELREIHNKQQLQKQKSMEAERLKQKEQERKIIELEKQKEEAQRRAQERDKQW
  LEHVQQEDEHQRPRKLHEEEKLKREESVKKKDGEEKGKQEAQDKLGRLFHQHQEPAKPAV
  QAPWSTAEKGPLTISAQENVKVVYYRALYPFESRSHDEITIQPGDIVMVKGEWVDESQTG
  EPGWLGGELKGKTGWFPANYAEKIPENEVPAPVKPVTDSTSAPAPKLALRETPAPLAVTS
  SEPSTTPNNWADFSSTWPTSTNEKPETDNWDAWAAQPSLTVPSAGQLRQRSAFTPATATG
  SSPSPVLGQGEKVEGLQAQALYPWRAKKDNHLNFNKNDVITVLEQQDMWWFGEVQGQKGW
  FPKSYVKLISGPIRKSTSMDSGSSESPASLKRVASPAAKPVVSGEEFIAMYTYESSEQGD
  LTFQQGDVILVTKKDGDWWTGTVGDKAGVFPSNYVRLKDSEGSGTAGKTGSLGKKPEIAQ
  VIASYTATGPEQLTLAPGQLILIRKKNPGGWWEGELQARGKKRQIGWFPANYVKLLSPGT
  SKITPTEPPKSTALAAVCQVIGMYDYTAQNDDELAFNKGQIINVLNKEDPDWWKGEVNGQ
  VGLFPSNYVKLTTDMDPSQQWCSDLHLLDMLTPTERKRQGYIHELIVTEENYVNDLQLVT
  EIFQKPLMESELLTEKEVAMIFVNWKELIMCNIKLLKALRVRKKMSGEKMPVKMIGDILS
  AQLPHMQPYIRFCSRQLNGAALIQQKTDEAPDFKEFVKRLAMDPRCKGMPLSSFILKPMQ
  RVTRYPLIIKNILENTPENHPDHSHLKHALEKAEELCSQVNEGVREKENSDRLEWIQAHV
  QCEGLSEQLVFNSVTNCLGPRKFLHSGKLYKAKSNKELYGFLFNDFLLLTQITKPLGSSG
  TDKVFSPKSNLQYKMYKTPIFLNEVLVKLPTDPSGDEPIFHISHIDRVYTLRAESINERT
  AWVQKIKAASELYIETEKKKREKAYLVRSQRATGIGRLMVNVVEGIELKPCRSHGKSNPY
  CEVTMGSQCHITKTIQDTLNPKWNSNCQFFIRDLEQEVLCITVFERDQFSPDDFLGRTEI
  RVADIKKDQGSKGPVTKCLLLHEVPTGEIVVRLDLQLFDEP
• Function: Adapter protein that provides a link between the endocytic membrane traffic and the actin assembly machinery. Acts as a guanine nucleotide exchange factor (GEF) for CDC42, and thereby stimulates actin nucleation mediated by WASL and the ARP2/3 complex. Plays a role in the assembly and maturation of clathrin-coated vesicles. Recruits FCHSD2 to clathrin-coated pits. Involved in endocytosis of activated EGFR, and probably also other growth factor receptors. Involved in endocytosis of integrin beta-1 (ITGB1) and transferrin receptor (TFR); internalization of ITGB1 as DAB2-dependent cargo but not TFR may involve association with DAB2. Promotes ubiquitination and subsequent degradation of EGFR, and thereby contributes to the down-regulation of EGFR-dependent signaling pathways. In chromaffin cells, required for normal exocytosis of catecholamines. Required for rapid replenishment of release-ready synaptic vesicles at presynaptic active zones. Inhibits ARHGAP31 activity toward RAC1 ; [Isoform 1]: Plays a role in synaptic vesicle endocytosis in brain neurons.
• Tissue Specificity: Isoform 1 is expressed almost exclusively in the brain. Isoform 2 is detected in brain, spleen, lung, liver, heart, skeletal muscle and kidney. Isoform 5 is primarily expressed in brain, spleen, lung and kidney (at protein level) . Isoform 1 and isoform 2 are detected in brain . Isoform 2 is ubiquitous in adult and fetal tissues with high expression in skeletal muscle, heart, spleen, ovary, testis and all fetal tissues tested and low expression in thymus, blood, lung, liver and pancreas. Isoform 1 is expressed almost exclusively in the brain, in all brain regions. Not expressed in the spinal cord .
• Reactome Pathway:
  EPHB-mediated forward signaling (R-HSA-3928662)
  G alpha (12/13) signalling events (R-HSA-416482)
  Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825)
  Clathrin-mediated endocytosis (R-HSA-8856828)
  CDC42 GTPase cycle (R-HSA-9013148)
  RHOQ GTPase cycle (R-HSA-9013406)
  RHOG GTPase cycle (R-HSA-9013408)
  NRAGE signals death through JNK (R-HSA-193648)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Coronary heart disease	DIS5OIP1	Definitive	Altered Expression	[1]
Rheumatoid arthritis	DISTSB4J	Definitive	Altered Expression	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Androgen insensitivity syndrome	DISUZBBO	Strong	Altered Expression	[4]
Arterial disorder	DISLG4XS	Strong	Biomarker	[5]
Glioma	DIS5RPEH	Strong	Biomarker	[6]
Lung cancer	DISCM4YA	Strong	Biomarker	[7]
Lung carcinoma	DISTR26C	Strong	Biomarker	[7]
Prostate cancer	DISF190Y	Strong	Biomarker	[8]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[8]
Pulmonary disease	DIS6060I	Strong	Biomarker	[9]
Adult glioblastoma	DISVP4LU	moderate	Altered Expression	[10]
Breast cancer	DIS7DPX1	moderate	Biomarker	[11]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[11]
Glioblastoma multiforme	DISK8246	moderate	Altered Expression	[10]
Intellectual disability	DISMBNXP	Limited	Biomarker	[12]
Isolated congenital microcephaly	DISUXHZ6	Limited	Biomarker	[12]
Neoplasm	DISZKGEW	Limited	Biomarker	[13]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[13]
Pulmonary arterial hypertension	DISP8ZX5	Limited	Biomarker	[7]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Intersectin-1 (ITSN1) affects the response to substance of Fluorouracil.	[27]

10 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 Intersectin-1 (ITSN1).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Intersectin-1 (ITSN1).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Intersectin-1 (ITSN1).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Intersectin-1 (ITSN1).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Intersectin-1 (ITSN1).	[18]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Intersectin-1 (ITSN1).	[19]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Intersectin-1 (ITSN1).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Intersectin-1 (ITSN1).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Intersectin-1 (ITSN1).	[24]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Intersectin-1 (ITSN1).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Intersectin-1 (ITSN1).	[21]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Intersectin-1 (ITSN1).	[23]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of Intersectin-1 (ITSN1).	[25]

References

• [1] Circulating lncRNA IFNG-AS1 expression correlates with increased disease risk, higher disease severity and elevated inflammation in patients with coronary artery disease.J Clin Lab Anal. 2018 Sep;32(7):e22452. doi: 10.1002/jcla.22452. Epub 2018 May 9.
• [2] Downregulation of lncRNA ITSN1-2 correlates with decreased disease risk and activity of rheumatoid arthritis (RA), and reduces RA fibroblast-like synoviocytes proliferation and inflammation via inhibiting NOD2/RIP2 signaling pathway.Am J Transl Res. 2019 Aug 15;11(8):4650-4666. eCollection 2019.
• [3] Intersectin 1 contributes to phenotypes in vivo: implications for Down's syndrome.Neuroreport. 2011 Oct 26;22(15):767-72. doi: 10.1097/WNR.0b013e32834ae348.
• [4] The correlation of long non-coding RNA intersectin 1-2 with disease risk, disease severity, inflammation, and prognosis of acute ischemic stroke.J Clin Lab Anal. 2020 Feb;34(2):e23053. doi: 10.1002/jcla.23053. Epub 2019 Oct 24.
• [5] Modulation of Intersectin-1s Lung Expression Induces Obliterative Remodeling and Severe Plexiform Arteriopathy in the Murine Pulmonary Vascular Bed.Am J Pathol. 2017 Mar;187(3):528-542. doi: 10.1016/j.ajpath.2016.11.012. Epub 2017 Jan 6.
• [6] Alternative splicing-derived intersectin1-L and intersectin1-S exert opposite function in glioma progression.Cell Death Dis. 2019 Jun 3;10(6):431. doi: 10.1038/s41419-019-1668-0.
• [7] Intersectin-1s deficiency in pulmonary pathogenesis.Respir Res. 2017 Sep 6;18(1):168. doi: 10.1186/s12931-017-0652-4.
• [8] The long tail of oncogenic drivers in prostate cancer.Nat Genet. 2018 May;50(5):645-651. doi: 10.1038/s41588-018-0078-z. Epub 2018 Apr 2.
• [9] Rac1-mediated cytoskeleton rearrangements induced by intersectin-1s deficiency promotes lung cancer cell proliferation, migration and metastasis.Mol Cancer. 2016 Sep 14;15(1):59. doi: 10.1186/s12943-016-0543-1.
• [10] Intersectin1-S, a multidomain adapter protein, is essential for malignant glioma proliferation.Glia. 2015 Sep;63(9):1595-605. doi: 10.1002/glia.22830. Epub 2015 Apr 2.
• [11] Intersectin 1 (ITSN1) identified by comprehensive bioinformatic analysis and experimental validation as a key candidate biological target in breast cancer.Onco Targets Ther. 2019 Aug 30;12:7079-7093. doi: 10.2147/OTT.S216286. eCollection 2019.
• [12] A de novo 1.4-Mb deletion at 21q22.11 in a boy with developmental delay.Am J Med Genet A. 2014 Apr;164A(4):1021-8. doi: 10.1002/ajmg.a.36377. Epub 2014 Jan 23.
• [13] Silencing Intersectin 1 Slows Orthotopic Neuroblastoma Growth in Mice.J Pediatr Hematol Oncol. 2017 Nov;39(8):e413-e418. doi: 10.1097/MPH.0000000000000931.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [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] 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.
• [20] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [25] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.
• [26] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [27] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.