Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFL3PUX)

• DOT Name: Protein lin-7 homolog A (LIN7A)
• Synonyms: Lin-7A; hLin-7; Mammalian lin-seven protein 1; MALS-1; Tax interaction protein 33; TIP-33; Vertebrate lin-7 homolog 1; Veli-1
• Gene Name: LIN7A
• Related Disease:
  Advanced cancer
  Attention deficit hyperactivity disorder
  Breast carcinoma
  Epithelial ovarian cancer
  Huntington disease
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Carcinoma
  Hepatocellular carcinoma
  Intellectual disability
  Undifferentiated carcinoma
• UniProt ID: LIN7A_HUMAN
• Pfam ID: PF02828 ; PF00595
• Sequence:
  MLKPSVTSAPTADMATLTVVQPLTLDRDVARAIELLEKLQESGEVPVHKLQSLKKVLQSE
  FCTAIREVYQYMHETITVNGCPEFRARATAKATVAAFAASEGHSHPRVVELPKTDEGLGF
  NVMGGKEQNSPIYISRIIPGGVAERHGGLKRGDQLLSVNGVSVEGEHHEKAVELLKAAKD
  SVKLVVRYTPKVLEEMEARFEKLRTARRRQQQQLLIQQQQQQQQQQTQQNHMS
• Function: Plays a role in establishing and maintaining the asymmetric distribution of channels and receptors at the plasma membrane of polarized cells. Forms membrane-associated multiprotein complexes that may regulate delivery and recycling of proteins to the correct membrane domains. The tripartite complex composed of LIN7 (LIN7A, LIN7B or LIN7C), CASK and APBA1 associates with the motor protein KIF17 to transport vesicles containing N-methyl-D-aspartate (NMDA) receptor subunit NR2B along microtubules. This complex may have the potential to couple synaptic vesicle exocytosis to cell adhesion in brain. Ensures the proper localization of GRIN2B (subunit 2B of the NMDA receptor) to neuronal postsynaptic density and may function in localizing synaptic vesicles at synapses where it is recruited by beta-catenin and cadherin. Required to localize Kir2 channels, GABA transporter (SLC6A12) and EGFR/ERBB1, ERBB2, ERBB3 and ERBB4 to the basolateral membrane of epithelial cells.
• Tissue Specificity: Expressed in brain, testis, kidney, placenta and liver.
• Reactome Pathway:
  Neurexins and neuroligins (R-HSA-6794361)
  Assembly and cell surface presentation of NMDA receptors (R-HSA-9609736)
  Dopamine Neurotransmitter Release Cycle (R-HSA-212676)

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]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[1]
Huntington disease	DISQPLA4	Strong	Altered Expression	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[1]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[1]
Carcinoma	DISH9F1N	Limited	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[7]
Intellectual disability	DISMBNXP	Limited	Biomarker	[8]
Undifferentiated carcinoma	DISIAZST	Limited	Biomarker	[6]

21 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 Protein lin-7 homolog A (LIN7A).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein lin-7 homolog A (LIN7A).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protein lin-7 homolog A (LIN7A).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein lin-7 homolog A (LIN7A).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein lin-7 homolog A (LIN7A).	[13]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Protein lin-7 homolog A (LIN7A).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Protein lin-7 homolog A (LIN7A).	[15]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Protein lin-7 homolog A (LIN7A).	[9]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Protein lin-7 homolog A (LIN7A).	[15]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Protein lin-7 homolog A (LIN7A).	[16]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Protein lin-7 homolog A (LIN7A).	[17]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Protein lin-7 homolog A (LIN7A).	[18]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Protein lin-7 homolog A (LIN7A).	[19]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Protein lin-7 homolog A (LIN7A).	[20]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Protein lin-7 homolog A (LIN7A).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein lin-7 homolog A (LIN7A).	[23]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Protein lin-7 homolog A (LIN7A).	[24]
SB-431542	DM0YOXQ	Preclinical	SB-431542 increases the expression of Protein lin-7 homolog A (LIN7A).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Protein lin-7 homolog A (LIN7A).	[27]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Protein lin-7 homolog A (LIN7A).	[18]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Protein lin-7 homolog A (LIN7A).	[28]

2 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 increases the methylation of Protein lin-7 homolog A (LIN7A).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Protein lin-7 homolog A (LIN7A).	[26]

References

• [1] Long noncoding RNA CASC9 promotes LIN7A expression via miR-758-3p to facilitate the malignancy of ovarian cancer.J Cell Physiol. 2019 Jul;234(7):10800-10808. doi: 10.1002/jcp.27903. Epub 2018 Dec 7.
• [2] Association study of brain-derived neurotrophic factor (BDNF) and LIN-7 homolog (LIN-7) genes with adult attention-deficit/hyperactivity disorder.Am J Med Genet B Neuropsychiatr Genet. 2008 Sep 5;147B(6):945-51. doi: 10.1002/ajmg.b.30723.
• [3] LIN7A is a major determinant of cell-polarity defects in breast carcinomas.Breast Cancer Res. 2016 Feb 17;18(1):23. doi: 10.1186/s13058-016-0680-x.
• [4] Decreased Lin7b expression in layer 5 pyramidal neurons may contribute to impaired corticostriatal connectivity in huntington disease.J Neuropathol Exp Neurol. 2010 Sep;69(9):880-95. doi: 10.1097/NEN.0b013e3181ed7a41.
• [5] The Drosophila TNF receptor Grindelwald couples loss of cell polarity and neoplastic growth.Nature. 2015 Jun 25;522(7557):482-6. doi: 10.1038/nature14298. Epub 2015 Apr 15.
• [6] cDNA microarray profiling of rat mammary gland carcinomas induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and 7,12-dimethylbenz[a]anthracene.Carcinogenesis. 2002 Oct;23(10):1561-8. doi: 10.1093/carcin/23.10.1561.
• [7] microRNA-501-3p suppresses metastasis and progression of hepatocellular carcinoma through targeting LIN7A.Cell Death Dis. 2018 May 1;9(5):535. doi: 10.1038/s41419-018-0577-y.
• [8] LIN7A depletion disrupts cerebral cortex development, contributing to intellectual disability in 12q21-deletion syndrome.PLoS One. 2014 Mar 21;9(3):e92695. doi: 10.1371/journal.pone.0092695. eCollection 2014.
• [9] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [10] 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.
• [11] 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.
• [12] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [13] 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.
• [14] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [15] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [16] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [17] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [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] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [23] 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.
• [24] 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.
• [25] Activin/nodal signaling switches the terminal fate of human embryonic stem cell-derived trophoblasts. J Biol Chem. 2015 Apr 3;290(14):8834-48.
• [26] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [27] 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.
• [28] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.