Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYNHP9E)

• DOT Name: Leucine-rich repeat transmembrane protein FLRT1 (FLRT1)
• Synonyms: Fibronectin-like domain-containing leucine-rich transmembrane protein 1
• Gene Name: FLRT1
• Related Disease: Spastic paraplegia, optic atropy, and neuropathy
• UniProt ID: FLRT1_HUMAN
• Pfam ID: PF13855 ; PF01462
• Sequence:
  MVVAHPTATATTTPTATVTATVVMTTATMDLRDWLFLCYGLIAFLTEVIDSTTCPSVCRC
  DNGFIYCNDRGLTSIPADIPDDATTLYLQNNQINNAGIPQDLKTKVNVQVIYLYENDLDE
  FPINLPRSLRELHLQDNNVRTIARDSLARIPLLEKLHLDDNSVSTVSIEEDAFADSKQLK
  LLFLSRNHLSSIPSGLPHTLEELRLDDNRISTIPLHAFKGLNSLRRLVLDGNLLANQRIA
  DDTFSRLQNLTELSLVRNSLAAPPLNLPSAHLQKLYLQDNAISHIPYNTLAKMRELERLD
  LSNNNLTTLPRGLFDDLGNLAQLLLRNNPWFCGCNLMWLRDWVKARAAVVNVRGLMCQGP
  EKVRGMAIKDITSEMDECFETGPQGGVANAAAKTTASNHASATTPQGSLFTLKAKRPGLR
  LPDSNIDYPMATGDGAKTLAIHVKALTADSIRITWKATLPASSFRLSWLRLGHSPAVGSI
  TETLVQGDKTEYLLTALEPKSTYIICMVTMETSNAYVADETPVCAKAETADSYGPTTTLN
  QEQNAGPMASLPLAGIIGGAVALVFLFLVLGAICWYVHQAGELLTRERAYNRGSRKKDDY
  MESGTKKDNSILEIRGPGLQMLPINPYRAKEEYVVHTIFPSNGSSLCKATHTIGYGTTRG
  YRDGGIPDIDYSYT
• Function: Plays a role in fibroblast growth factor-mediated signaling cascades that lead to the activation of MAP kinases. Promotes neurite outgrowth via FGFR1-mediated activation of downstream MAP kinases. Promotes an increase both in neurite number and in neurite length. May play a role in cell-cell adhesion and cell guidance via its interaction with ADGRL1/LPHN1 and ADGRL3.
• Tissue Specificity: Expressed in kidney and brain.
• Reactome Pathway: Downstream signaling of activated FGFR1 (R-HSA-5654687)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Spastic paraplegia, optic atropy, and neuropathy	DIS0Q1EV	Supportive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Leucine-rich repeat transmembrane protein FLRT1 (FLRT1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Leucine-rich repeat transmembrane protein FLRT1 (FLRT1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Leucine-rich repeat transmembrane protein FLRT1 (FLRT1).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Leucine-rich repeat transmembrane protein FLRT1 (FLRT1).	[5]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Leucine-rich repeat transmembrane protein FLRT1 (FLRT1).	[6]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Leucine-rich repeat transmembrane protein FLRT1 (FLRT1).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Leucine-rich repeat transmembrane protein FLRT1 (FLRT1).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Leucine-rich repeat transmembrane protein FLRT1 (FLRT1).	[9]

References

• [1] Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science. 2014 Jan 31;343(6170):506-511. doi: 10.1126/science.1247363.
• [2] 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.
• [3] 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.
• [4] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] 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.
• [7] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [8] 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.
• [9] 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.