Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT05J514)

• DOT Name: Iroquois-class homeodomain protein IRX-5 (IRX5)
• Synonyms: Homeodomain protein IRX-2A; Homeodomain protein IRXB2; Iroquois homeobox protein 5
• Gene Name: IRX5
• Related Disease:
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Craniofacial dysplasia - osteopenia syndrome
  Frontonasal dysplasia
  Hypochromic microcytic anemia
  Lacrimal apparatus disorder
  Lung adenocarcinoma
  Myopia
  Neoplasm
  Non-small-cell lung cancer
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Rheumatoid arthritis
  Sensorineural hearing loss disorder
  Tooth agenesis
  Tooth agenesis, selective, 1
  Wilms tumor
  Obesity
  Retinitis pigmentosa
  Hepatocellular carcinoma
  Pulmonary disease
• UniProt ID: IRX5_HUMAN
• Pfam ID: PF05920
• Sequence:
  MSYPQGYLYQPSASLALYSCPAYSTSVISGPRTDELGRSSSGSAFSPYAGSTAFTAPSPG
  YNSHLQYGADPAAAAAAAFSSYVGSPYDHTPGMAGSLGYHPYAAPLGSYPYGDPAYRKNA
  TRDATATLKAWLNEHRKNPYPTKGEKIMLAIITKMTLTQVSTWFANARRRLKKENKMTWT
  PRNRSEDEEEEENIDLEKNDEDEPQKPEDKGDPEGPEAGGAEQKAASGCERLQGPPTPAG
  KETEGSLSDSDFKEPPSEGRLDALQGPPRTGGPSPAGPAAARLAEDPAPHYPAGAPAPGP
  HPAAGEVPPGPGGPSVIHSPPPPPPPAVLAKPKLWSLAEIATSSDKVKDGGGGNEGSPCP
  PCPGPIAGQALGGSRASPAPAPSRSPSAQCPFPGGTVLSRPLYYTAPFYPGYTNYGSFGH
  LHGHPGPGPGPTTGPGSHFNGLNQTVLNRADALAKDPKMLRSQSQLDLCKDSPYELKKGM
  SDI
• Function: Establishes the cardiac repolarization gradient by its repressive actions on the KCND2 potassium-channel gene. Required for retinal cone bipolar cell differentiation. May regulate contrast adaptation in the retina and control specific aspects of visual function in circuits of the mammalian retina. Could be involved in the regulation of both the cell cycle and apoptosis in prostate cancer cells. Involved in craniofacial and gonadal development. Modulates the migration of progenitor cell populations in branchial arches and gonads by repressing CXCL12.

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colon cancer	DISVC52G	Strong	Biomarker	[1]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[2]
Craniofacial dysplasia - osteopenia syndrome	DISAACI7	Strong	Autosomal recessive	[3]
Frontonasal dysplasia	DISXV4YX	Strong	Biomarker	[4]
Hypochromic microcytic anemia	DIS0RMTQ	Strong	Biomarker	[4]
Lacrimal apparatus disorder	DIS83E37	Strong	Biomarker	[4]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[5]
Myopia	DISK5S60	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[5]
Prostate cancer	DISF190Y	Strong	Altered Expression	[1]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[1]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[1]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[7]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Biomarker	[4]
Tooth agenesis	DIS1PWC7	Strong	Biomarker	[4]
Tooth agenesis, selective, 1	DIS84ERL	Strong	Biomarker	[4]
Wilms tumor	DISB6T16	Strong	Biomarker	[8]
Obesity	DIS47Y1K	moderate	Altered Expression	[9]
Retinitis pigmentosa	DISCGPY8	moderate	Biomarker	[10]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[11]
Pulmonary disease	DIS6060I	Limited	Biomarker	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Iroquois-class homeodomain protein IRX-5 (IRX5).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Iroquois-class homeodomain protein IRX-5 (IRX5).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Iroquois-class homeodomain protein IRX-5 (IRX5).	[15]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Iroquois-class homeodomain protein IRX-5 (IRX5).	[16]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Iroquois-class homeodomain protein IRX-5 (IRX5).	[17]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Iroquois-class homeodomain protein IRX-5 (IRX5).	[18]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Iroquois-class homeodomain protein IRX-5 (IRX5).	[19]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of Iroquois-class homeodomain protein IRX-5 (IRX5).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Iroquois-class homeodomain protein IRX-5 (IRX5).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Iroquois-class homeodomain protein IRX-5 (IRX5).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Iroquois-class homeodomain protein IRX-5 (IRX5).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Iroquois-class homeodomain protein IRX-5 (IRX5).	[24]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Iroquois-class homeodomain protein IRX-5 (IRX5).	[25]

References

• [1] The iroquois homeobox gene 5 is regulated by 1,25-dihydroxyvitamin D3 in human prostate cancer and regulates apoptosis and the cell cycle in LNCaP prostate cancer cells.Clin Cancer Res. 2008 Jun 1;14(11):3562-70. doi: 10.1158/1078-0432.CCR-07-4649.
• [2] IRX5 promotes colorectal cancer metastasis by negatively regulating the core components of the RHOA pathway.Mol Carcinog. 2019 Nov;58(11):2065-2076. doi: 10.1002/mc.23098. Epub 2019 Aug 20.
• [3] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [4] Mutations in IRX5 impair craniofacial development and germ cell migration via SDF1. Nat Genet. 2012 May 13;44(6):709-13. doi: 10.1038/ng.2259.
• [5] Genome-wide identification of transcription factors that are critical to non-small cell lung cancer.Cancer Lett. 2018 Oct 10;434:132-143. doi: 10.1016/j.canlet.2018.07.020. Epub 2018 Jul 18.
• [6] VSTM2A Overexpression Is a Sensitive and Specific Biomarker for Mucinous Tubular and Spindle Cell Carcinoma (MTSCC) of the Kidney.Am J Surg Pathol. 2018 Dec;42(12):1571-1584. doi: 10.1097/PAS.0000000000001150.
• [7] Iroquois transcription factor irx2a is required for multiciliated and transporter cell fate decisions during zebrafish pronephros development.Sci Rep. 2019 Apr 23;9(1):6454. doi: 10.1038/s41598-019-42943-y.
• [8] The Iroquois homeobox proteins IRX3 and IRX5 have distinct roles in Wilms tumour development and human nephrogenesis.J Pathol. 2019 Jan;247(1):86-98. doi: 10.1002/path.5171. Epub 2018 Nov 29.
• [9] IRX5 regulates adipocyte amyloid precursor protein and mitochondrial respiration in obesity.Int J Obes (Lond). 2019 Nov;43(11):2151-2162. doi: 10.1038/s41366-018-0275-y. Epub 2018 Dec 11.
• [10] Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease.Am J Hum Genet. 2017 Jan 5;100(1):75-90. doi: 10.1016/j.ajhg.2016.12.003. Epub 2016 Dec 29.
• [11] Long-Noncoding RNA Colorectal Neoplasia Differentially Expressed Gene as a Potential Target to Upregulate the Expression of IRX5 by miR-136-5P to Promote Oncogenic Properties in Hepatocellular Carcinoma.Cell Physiol Biochem. 2018;50(6):2229-2248. doi: 10.1159/000495084. Epub 2018 Nov 13.
• [12] Expression of Iroquois genes is up-regulated during early lung development in the nitrofen-induced pulmonary hypoplasia.J Pediatr Surg. 2011 Jan;46(1):62-6. doi: 10.1016/j.jpedsurg.2010.09.059.
• [13] 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.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] 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.
• [17] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [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] 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.
• [25] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.