Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3XMZU3)

• DOT Name: Leucine-rich repeat transmembrane protein FLRT3 (FLRT3)
• Synonyms: Fibronectin-like domain-containing leucine-rich transmembrane protein 3
• Gene Name: FLRT3
• Related Disease:
  Attention deficit hyperactivity disorder
  Congenital hypogonadotropic hypogonadism
  Neuralgia
  Kallmann syndrome
  Hypogonadotropic hypogonadism 21 with or without anosmia
• UniProt ID: FLRT3_HUMAN
• PDB ID: 5CMN; 5CMP; 6JBU
• Pfam ID: PF13855
• Sequence:
  MISAAWSIFLIGTKIGLFLQVAPLSVMAKSCPSVCRCDAGFIYCNDRFLTSIPTGIPEDA
  TTLYLQNNQINNAGIPSDLKNLLKVERIYLYHNSLDEFPTNLPKYVKELHLQENNIRTIT
  YDSLSKIPYLEELHLDDNSVSAVSIEEGAFRDSNYLRLLFLSRNHLSTIPWGLPRTIEEL
  RLDDNRISTISSPSLQGLTSLKRLVLDGNLLNNHGLGDKVFFNLVNLTELSLVRNSLTAA
  PVNLPGTNLRKLYLQDNHINRVPPNAFSYLRQLYRLDMSNNNLSNLPQGIFDDLDNITQL
  ILRNNPWYCGCKMKWVRDWLQSLPVKVNVRGLMCQAPEKVRGMAIKDLNAELFDCKDSGI
  VSTIQITTAIPNTVYPAQGQWPAPVTKQPDIKNPKLTKDHQTTGSPSRKTITITVKSVTS
  DTIHISWKLALPMTALRLSWLKLGHSPAFGSITETIVTGERSEYLVTALEPDSPYKVCMV
  PMETSNLYLFDETPVCIETETAPLRMYNPTTTLNREQEKEPYKNPNLPLAAIIGGAVALV
  TIALLALVCWYVHRNGSLFSRNCAYSKGRRRKDDYAEAGTKKDNSILEIRETSFQMLPIS
  NEPISKEEFVIHTIFPPNGMNLYKNNHSESSSNRSYRDSGIPDSDHSHS
• Function: Functions in cell-cell adhesion, cell migration and axon guidance, exerting an attractive or repulsive role depending on its interaction partners. Plays a role in the spatial organization of brain neurons. Plays a role in vascular development in the retina. Plays a role in cell-cell adhesion via its interaction with ADGRL3 and probably also other latrophilins that are expressed at the surface of adjacent cells. Interaction with the intracellular domain of ROBO1 mediates axon attraction towards cells expressing NTN1. Mediates axon growth cone collapse and plays a repulsive role in neuron guidance via its interaction with UNC5B, and possibly also other UNC-5 family members. Promotes neurite outgrowth (in vitro). Mediates cell-cell contacts that promote an increase both in neurite number and in neurite length. Plays a role in the regulation of the density of glutamaergic synapses. Plays a role in fibroblast growth factor-mediated signaling cascades. Required for normal morphogenesis during embryonic development, but not for normal embryonic patterning. Required for normal ventral closure, headfold fusion and definitive endoderm migration during embryonic development. Required for the formation of a normal basement membrane and the maintenance of a normal anterior visceral endoderm during embryonic development.
• Tissue Specificity: Expressed in kidney, brain, pancreas, skeletal muscle, lung, liver, placenta, and heart.
• Reactome Pathway:
  Downstream signaling of activated FGFR1 (R-HSA-5654687)
  Signaling by ROBO receptors (R-HSA-376176)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Genetic Variation	[1]
Congenital hypogonadotropic hypogonadism	DISEV092	Strong	Biomarker	[2]
Neuralgia	DISWO58J	Strong	Biomarker	[3]
Kallmann syndrome	DISO3HDG	Supportive	Autosomal dominant	[2]
Hypogonadotropic hypogonadism 21 with or without anosmia	DISTTKY0	Limited	Unknown	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitoxantrone	DMM39BF	Approved	Leucine-rich repeat transmembrane protein FLRT3 (FLRT3) affects the response to substance of Mitoxantrone.	[26]

25 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 Leucine-rich repeat transmembrane protein FLRT3 (FLRT3).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Leucine-rich repeat transmembrane protein FLRT3 (FLRT3).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Leucine-rich repeat transmembrane protein FLRT3 (FLRT3).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Leucine-rich repeat transmembrane protein FLRT3 (FLRT3).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Leucine-rich repeat transmembrane protein FLRT3 (FLRT3).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Leucine-rich repeat transmembrane protein FLRT3 (FLRT3).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Leucine-rich repeat transmembrane protein FLRT3 (FLRT3).	[10]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Leucine-rich repeat transmembrane protein FLRT3 (FLRT3).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Leucine-rich repeat transmembrane protein FLRT3 (FLRT3).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Leucine-rich repeat transmembrane protein FLRT3 (FLRT3).	[13]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Leucine-rich repeat transmembrane protein FLRT3 (FLRT3).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Leucine-rich repeat transmembrane protein FLRT3 (FLRT3).	[15]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Leucine-rich repeat transmembrane protein FLRT3 (FLRT3).	[16]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Leucine-rich repeat transmembrane protein FLRT3 (FLRT3).	[14]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Leucine-rich repeat transmembrane protein FLRT3 (FLRT3).	[17]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Leucine-rich repeat transmembrane protein FLRT3 (FLRT3).	[18]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Leucine-rich repeat transmembrane protein FLRT3 (FLRT3).	[19]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Leucine-rich repeat transmembrane protein FLRT3 (FLRT3).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Leucine-rich repeat transmembrane protein FLRT3 (FLRT3).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Leucine-rich repeat transmembrane protein FLRT3 (FLRT3).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Leucine-rich repeat transmembrane protein FLRT3 (FLRT3).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Leucine-rich repeat transmembrane protein FLRT3 (FLRT3).	[4]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Leucine-rich repeat transmembrane protein FLRT3 (FLRT3).	[23]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Leucine-rich repeat transmembrane protein FLRT3 (FLRT3).	[24]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Leucine-rich repeat transmembrane protein FLRT3 (FLRT3).	[25]

References

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• [2] Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. Am J Hum Genet. 2013 May 2;92(5):725-43. doi: 10.1016/j.ajhg.2013.04.008.
• [3] Increased Expression of Fibronectin Leucine-Rich Transmembrane Protein 3 in the Dorsal Root Ganglion Induces Neuropathic Pain in Rats.J Neurosci. 2019 Sep 18;39(38):7615-7627. doi: 10.1523/JNEUROSCI.0295-19.2019. Epub 2019 Jul 25.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] 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.
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• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
• [14] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [15] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [16] 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.
• [17] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [18] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [19] Gene expression in human hippocampus from cocaine abusers identifies genes which regulate extracellular matrix remodeling. PLoS One. 2007 Nov 14;2(11):e1187. doi: 10.1371/journal.pone.0001187.
• [20] Effect of benzo[a]pyrene on proliferation and metastasis of oral squamous cell carcinoma cells: A transcriptome analysis based on RNA-seq. Environ Toxicol. 2022 Nov;37(11):2589-2604. doi: 10.1002/tox.23621. Epub 2022 Jul 23.
• [21] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [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] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [24] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [25] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [26] 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.