Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGD8TID)

• DOT Name: Leucine-rich repeat transmembrane protein FLRT2 (FLRT2)
• Synonyms: Fibronectin-like domain-containing leucine-rich transmembrane protein 2
• Gene Name: FLRT2
• Related Disease:
  Breast cancer
  Breast carcinoma
  Prostate cancer
  Prostate carcinoma
  Advanced cancer
  Neoplasm
  Obstructive sleep apnea
  Systemic lupus erythematosus
• UniProt ID: FLRT2_HUMAN
• Pfam ID: PF00041 ; PF13855 ; PF01463
• Sequence:
  MGLQTTKWPSHGAFFLKSWLIISLGLYSQVSKLLACPSVCRCDRNFVYCNERSLTSVPLG
  IPEGVTVLYLHNNQINNAGFPAELHNVQSVHTVYLYGNQLDEFPMNLPKNVRVLHLQENN
  IQTISRAALAQLLKLEELHLDDNSISTVGVEDGAFREAISLKLLFLSKNHLSSVPVGLPV
  DLQELRVDENRIAVISDMAFQNLTSLERLIVDGNLLTNKGIAEGTFSHLTKLKEFSIVRN
  SLSHPPPDLPGTHLIRLYLQDNQINHIPLTAFSNLRKLERLDISNNQLRMLTQGVFDNLS
  NLKQLTARNNPWFCDCSIKWVTEWLKYIPSSLNVRGFMCQGPEQVRGMAVRELNMNLLSC
  PTTTPGLPLFTPAPSTASPTTQPPTLSIPNPSRSYTPPTPTTSKLPTIPDWDGRERVTPP
  ISERIQLSIHFVNDTSIQVSWLSLFTVMAYKLTWVKMGHSLVGGIVQERIVSGEKQHLSL
  VNLEPRSTYRICLVPLDAFNYRAVEDTICSEATTHASYLNNGSNTASSHEQTTSHSMGSP
  FLLAGLIGGAVIFVLVVLLSVFCWHMHKKGRYTSQKWKYNRGRRKDDYCEAGTKKDNSIL
  EMTETSFQIVSLNNDQLLKGDFRLQPIYTPNGGINYTDCHIPNNMRYCNSSVPDLEHCHT
• Function: Functions in cell-cell adhesion, cell migration and axon guidance. Mediates cell-cell adhesion via its interactions with ADGRL3 and probably also other latrophilins that are expressed at the surface of adjacent cells. May play a role in the migration of cortical neurons during brain development via its interaction with UNC5D. Mediates axon growth cone collapse and plays a repulsive role in neuron guidance via its interaction with UNC5D, and possibly also other UNC-5 family members. Plays a role in fibroblast growth factor-mediated signaling cascades. Required for normal organization of the cardiac basement membrane during embryogenesis, and for normal embryonic epicardium and heart morphogenesis.
• Tissue Specificity: Expressed in pancreas, skeletal muscle, brain, and heart.
• Reactome Pathway: Downstream signaling of activated FGFR1 (R-HSA-5654687)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Biomarker	[1]
Breast carcinoma	DIS2UE88	Definitive	Biomarker	[1]
Prostate cancer	DISF190Y	Definitive	Biomarker	[2]
Prostate carcinoma	DISMJPLE	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Obstructive sleep apnea	DIS0SVD1	Strong	Biomarker	[4]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[5]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Leucine-rich repeat transmembrane protein FLRT2 (FLRT2) affects the response to substance of Methotrexate.	[25]
Fluorouracil	DMUM7HZ	Approved	Leucine-rich repeat transmembrane protein FLRT2 (FLRT2) affects the response to substance of Fluorouracil.	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Leucine-rich repeat transmembrane protein FLRT2 (FLRT2).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Leucine-rich repeat transmembrane protein FLRT2 (FLRT2).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Leucine-rich repeat transmembrane protein FLRT2 (FLRT2).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Leucine-rich repeat transmembrane protein FLRT2 (FLRT2).	[8]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Leucine-rich repeat transmembrane protein FLRT2 (FLRT2).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Leucine-rich repeat transmembrane protein FLRT2 (FLRT2).	[10]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Leucine-rich repeat transmembrane protein FLRT2 (FLRT2).	[11]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Leucine-rich repeat transmembrane protein FLRT2 (FLRT2).	[12]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Leucine-rich repeat transmembrane protein FLRT2 (FLRT2).	[13]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Leucine-rich repeat transmembrane protein FLRT2 (FLRT2).	[14]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Leucine-rich repeat transmembrane protein FLRT2 (FLRT2).	[15]
Phenytoin	DMNOKBV	Approved	Phenytoin increases the expression of Leucine-rich repeat transmembrane protein FLRT2 (FLRT2).	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Leucine-rich repeat transmembrane protein FLRT2 (FLRT2).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Leucine-rich repeat transmembrane protein FLRT2 (FLRT2).	[11]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Leucine-rich repeat transmembrane protein FLRT2 (FLRT2).	[19]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Leucine-rich repeat transmembrane protein FLRT2 (FLRT2).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Leucine-rich repeat transmembrane protein FLRT2 (FLRT2).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Leucine-rich repeat transmembrane protein FLRT2 (FLRT2).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Leucine-rich repeat transmembrane protein FLRT2 (FLRT2).	[23]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Leucine-rich repeat transmembrane protein FLRT2 (FLRT2).	[24]

References

• [1] Enhanced synaptic plasticity and spatial memory in female but not male FLRT2-haplodeficient mice.Sci Rep. 2018 Feb 27;8(1):3703. doi: 10.1038/s41598-018-22030-4.
• [2] Methylation profiling identified novel differentially methylated markers including OPCML and FLRT2 in prostate cancer.Epigenetics. 2016 Apr 2;11(4):247-58. doi: 10.1080/15592294.2016.1148867. Epub 2016 Feb 18.
• [3] Epigenetically regulated Fibronectin leucine rich transmembrane protein 2 (FLRT2) shows tumor suppressor activity in breast cancer cells.Sci Rep. 2017 Mar 21;7(1):272. doi: 10.1038/s41598-017-00424-0.
• [4] Gene expression profiles in peripheral blood mononuclear cells of Asian obstructive sleep apnea patients.Biomed J. 2014 Mar-Apr;37(2):60-70. doi: 10.4103/2319-4170.113188.
• [5] A novel autoantibody against fibronectin leucine-rich transmembrane protein 2 expressed on the endothelial cell surface identified by retroviral vector system in systemic lupus erythematosus.Arthritis Res Ther. 2012 Jul 2;14(4):R157. doi: 10.1186/ar3897.
• [6] 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.
• [7] 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.
• [8] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [9] Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Mol Biol Cell. 2004 Mar;15(3):1262-72. doi: 10.1091/mbc.e03-06-0360. Epub 2003 Dec 29.
• [10] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [11] 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.
• [12] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [13] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [14] Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
• [15] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [16] Role of phenytoin in wound healing: microarray analysis of early transcriptional responses in human dermal fibroblasts. Biochem Biophys Res Commun. 2004 Feb 13;314(3):661-6. doi: 10.1016/j.bbrc.2003.12.146.
• [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] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [20] The genome-wide expression profile of Scrophularia ningpoensis-treated thapsigargin-stimulated U-87MG cells. Neurotoxicology. 2009 May;30(3):368-76.
• [21] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [22] 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.
• [23] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.
• [24] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [25] 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.