Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN7XAUD)

• DOT Name: Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1)
• Synonyms: LRR FLII-interacting protein 1; GC-binding factor 2; TAR RNA-interacting protein
• Gene Name: LRRFIP1
• Related Disease:
  Colorectal carcinoma
  Glioblastoma multiforme
  Neoplasm
  Clear cell renal carcinoma
  Hepatocellular carcinoma
  Heroin dependence
  Intrahepatic cholangiocarcinoma
  Myocardial infarction
  Psoriasis
  Renal cell carcinoma
  Stroke
  Advanced cancer
  Lung cancer
  Lung carcinoma
  Autoimmune disease
  Obesity
  Pneumocystis pneumonia
  Schizophrenia
• UniProt ID: LRRF1_HUMAN
• PDB ID: 4H22
• Pfam ID: PF09738
• Sequence:
  MTSPAAAQSREIDCLSPEAQKLAEARLAAKRAARAEAREIRMKELERQQKEEDSERYSRR
  SRRNTSASDEDERMSVGSRGSLRVEERPEKDFTEKGSRNMPGLSAATLASLGGTSSRRGS
  GDTSISIDTEASIREIKELNELKDQIQDVEGKYMQGLKEMKDSLAEVEEKYKKAMVSNAQ
  LDNEKTNFMYQVDTLKDMLLELEEQLAESRRQYEEKNKEFEREKHAHSILQFQFAEVKEA
  LKQREEMLEKHGIILNSEIATNGETSDTLNNVGYQGPTKMTKEELNALKSTGDGTLGRAS
  EVEVKNEIVANVGKREILHNTEKEQHTEDTVKDCVDIEVFPAGENTEDQKSSEDTAPFLG
  TLAGATYEEQVQSQILESSSLPENTVQVESNEVMGAPDDRTRTPLEPSNCWSDLDGGNHT
  ENVGEAAVTQVEEQAGTVASCPLGHSDDTVYHDDKCMVEVPQELETSTGHSLEKEFTNQE
  AAEPKEVPAHSTEVGRDHNEEEGEETGLRDEKPIKTEVPGSPAGTEGNCQEATGPSTVDT
  QNEPLDMKEPDEEKSDQQGEALDSSQKKTKNKKKKNKKKKSPVPVETLKDVKKELTYQNT
  DLSEIKEEEQVKSTDRKSAVEAQNEVTENPKQKIAAESSENVDCPENPKIKLDGKLDQEG
  DDVQTAAEEVLADGDTLDFEDDTVQSSGPRAGGEELDEGVAKDNAKIDGATQSSPAEPKS
  EDADRCTLPEHESPSQDISDACEAESTERCEMSEHPSQTVRKALDSNSLENDDLSAPGRE
  PGHFNPESREDTRGGNEKGKSKEDCTMS
• Function: Transcriptional repressor which preferentially binds to the GC-rich consensus sequence (5'-AGCCCCCGGCG-3') and may regulate expression of TNF, EGFR and PDGFA. May control smooth muscle cells proliferation following artery injury through PDGFA repression. May also bind double-stranded RNA. Positively regulates Toll-like receptor (TLR) signaling in response to agonist probably by competing with the negative FLII regulator for MYD88-binding.
• Tissue Specificity: Ubiquitously expressed.
• Reactome Pathway:
  LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production (R-HSA-3134973)
  Signaling by FGFR1 in disease (R-HSA-5655302)
  Signaling by cytosolic FGFR1 fusion mutants (R-HSA-1839117)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Definitive	Biomarker	[1]
Glioblastoma multiforme	DISK8246	Definitive	Altered Expression	[2]
Neoplasm	DISZKGEW	Definitive	Genetic Variation	[3]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Heroin dependence	DISQ1H57	Strong	Biomarker	[6]
Intrahepatic cholangiocarcinoma	DIS6GOC8	Strong	Biomarker	[7]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[8]
Psoriasis	DIS59VMN	Strong	Biomarker	[9]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[4]
Stroke	DISX6UHX	Strong	Biomarker	[10]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[11]
Lung cancer	DISCM4YA	moderate	Biomarker	[12]
Lung carcinoma	DISTR26C	moderate	Biomarker	[12]
Autoimmune disease	DISORMTM	Limited	Biomarker	[10]
Obesity	DIS47Y1K	Limited	Biomarker	[10]
Pneumocystis pneumonia	DISFSOM3	Limited	Biomarker	[13]
Schizophrenia	DISSRV2N	No Known	Unknown	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1).	[20]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1).	[21]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide affects the expression of Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1).	[24]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1).	[25]
Marinol	DM70IK5	Approved	Marinol increases the expression of Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1).	[26]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1).	[27]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1).	[29]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1).	[30]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1).	[31]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1).	[32]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1).	[33]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1).	[34]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1).	[35]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1).	[38]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1).	[39]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1).	[22]
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1).	[23]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1).	[28]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1).	[36]
TAK-243	DM4GKV2	Phase 1	TAK-243 affects the sumoylation of Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1).	[37]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1).	[28]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1).	[23]

References

• [1] GCF2/LRRFIP1 promotes colorectal cancer metastasis and liver invasion through integrin-dependent RhoA activation.Cancer Lett. 2012 Dec 1;325(1):99-107. doi: 10.1016/j.canlet.2012.06.012. Epub 2012 Jun 28.
• [2] Higher LRRFIP1 expression in glioblastoma multiforme is associated with better response to teniposide, a type II topoisomerase inhibitor.Biochem Biophys Res Commun. 2014 Apr 18;446(4):1261-7. doi: 10.1016/j.bbrc.2014.03.105. Epub 2014 Mar 29.
• [3] Aptamer-derived peptides as potent inhibitors of the oncogenic RhoGEF Tgat.Chem Biol. 2009 Apr 24;16(4):391-400. doi: 10.1016/j.chembiol.2009.02.006.
• [4] MLN4924 (Pevonedistat), a protein neddylation inhibitor, suppresses proliferation and migration of human clear cell renal cell carcinoma.Sci Rep. 2017 Jul 17;7(1):5599. doi: 10.1038/s41598-017-06098-y.
• [5] Knockdown of GCF2/LRRFIP1 by RNAi causes cell growth inhibition and increased apoptosis in human hepatoma HepG2 cells.Asian Pac J Cancer Prev. 2014;15(6):2753-8. doi: 10.7314/apjcp.2014.15.6.2753.
• [6] Weighted gene co-expression network analysis to explore the mechanism of heroin addiction in human nucleus accumbens.J Cell Biochem. 2020 Feb;121(2):1870-1879. doi: 10.1002/jcb.29422. Epub 2019 Nov 6.
• [7] Knockdown of Nedd8conjugating enzyme UBE2M suppresses the proliferation and induces the apoptosis of intrahepatic cholangiocarcinoma cells.Oncol Rep. 2019 Dec;42(6):2670-2679. doi: 10.3892/or.2019.7327. Epub 2019 Sep 20.
• [8] Transcription profiling in human platelets reveals LRRFIP1 as a novel protein regulating platelet function.Blood. 2010 Nov 25;116(22):4646-56. doi: 10.1182/blood-2010-04-280925. Epub 2010 Sep 10.
• [9] Fumaric acid esters for psoriasis: a systematic review.Ir J Med Sci. 2017 Feb;186(1):161-177. doi: 10.1007/s11845-016-1470-2. Epub 2016 Jun 7.
• [10] Multidisciplinary Roles of LRRFIP1/GCF2 in Human Biological Systems and Diseases.Cells. 2019 Jan 31;8(2):108. doi: 10.3390/cells8020108.
• [11] Silencing of LRRFIP1 reverses the epithelial-mesenchymal transition via inhibition of the Wnt/-catenin signaling pathway.Cancer Lett. 2015 Aug 28;365(1):132-40. doi: 10.1016/j.canlet.2015.05.023. Epub 2015 Jun 3.
• [12] Systematic Analysis of Gene Expression Alterations and Clinical Outcomes for Long-Chain Acyl-Coenzyme A Synthetase Family in Cancer.PLoS One. 2016 May 12;11(5):e0155660. doi: 10.1371/journal.pone.0155660. eCollection 2016.
• [13] GC-binding factor 2 interacts with dishevelled and regulates Wnt signaling pathways in human carcinoma cell lines.Int J Cancer. 2011 Oct 1;129(7):1599-610. doi: 10.1002/ijc.25837. Epub 2011 Mar 8.
• [14] Identification of new schizophrenia susceptibility loci in an ethnically homogeneous, family-based, Arab-Israeli sample. FASEB J. 2011 Nov;25(11):4011-23. doi: 10.1096/fj.11-184937. Epub 2011 Jul 27.
• [15] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [16] 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.
• [17] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [18] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [19] 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.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] 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.
• [22] Effect of prenatal arsenic exposure on DNA methylation and leukocyte subpopulations in cord blood. Epigenetics. 2014 May;9(5):774-82. doi: 10.4161/epi.28153. Epub 2014 Feb 13.
• [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] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [25] 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.
• [26] JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene. 2008 Aug 28;27(37):5033-44.
• [27] 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.
• [28] 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.
• [29] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [30] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [31] Chronic ethanol exposure increases goosecoid (GSC) expression in human embryonic carcinoma cell differentiation. J Appl Toxicol. 2014 Jan;34(1):66-75.
• [32] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [33] 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.
• [34] Molecular mechanisms of resveratrol action in lung cancer cells using dual protein and microarray analyses. Cancer Res. 2007 Dec 15;67(24):12007-17. doi: 10.1158/0008-5472.CAN-07-2464.
• [35] Epigallocatechin-3-gallate (EGCG) protects against chromate-induced toxicity in vitro. Toxicol Appl Pharmacol. 2012 Jan 15;258(2):166-75.
• [36] 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.
• [37] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [38] 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.
• [39] 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.