Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLJ48FG)

• DOT Name: Iroquois-class homeodomain protein IRX-3 (IRX3)
• Synonyms: Homeodomain protein IRXB1; Iroquois homeobox protein 3
• Gene Name: IRX3
• Related Disease:
  Acute leukaemia
  Acute myelogenous leukaemia
  B-cell acute lymphoblastic leukaemia
  Breast cancer
  Breast carcinoma
  Hepatocellular carcinoma
  Lymphoid leukemia
  Obesity
  T-cell acute lymphoblastic leukaemia
  Ventricular tachycardia
  Wilms tumor
  Neoplasm
  Non-insulin dependent diabetes
  Pulmonary disease
• UniProt ID: IRX3_HUMAN
• Pfam ID: PF05920
• Sequence:
  MSFPQLGYQYIRPLYPSERPGAAGGSGGSAGARGGLGAGASELNASGSLSNVLSSVYGAP
  YAAAAAAAAAQGYGAFLPYAAELPIFPQLGAQYELKDSPGVQHPAAAAAFPHPHPAFYPY
  GQYQFGDPSRPKNATRESTSTLKAWLNEHRKNPYPTKGEKIMLAIITKMTLTQVSTWFAN
  ARRRLKKENKMTWAPRSRTDEEGNAYGSEREEEDEEEDEEDGKRELELEEEELGGEEEDT
  GGEGLADDDEDEEIDLENLDGAATEPELSLAGAARRDGDLGLGPISDSKNSDSEDSSEGL
  EDRPLPVLSLAPAPPPVAVASPSLPSPPVSLDPCAPAPAPASALQKPKIWSLAETATSPD
  NPRRSPPGAGGSPPGAAVAPSALQLSPAAAAAAAHRLVSAPLGKFPAWTNRPFPGPPPGP
  RLHPLSLLGSAPPHLLGLPGAAGHPAAAAAFARPAEPEGGTDRCSALEVEKKLLKTAFQP
  VPRRPQNHLDAALVLSALSSS
• Function: Transcription factor involved in SHH-dependent neural patterning. Together with NKX2-2 and NKX6-1 acts to restrict the generation of motor neurons to the appropriate region of the neural tube. Belongs to the class I proteins of neuronal progenitor factors, which are repressed by SHH signals. Involved in the transcriptional repression of MNX1 in non-motor neuron cells. Acts as a regulator of energy metabolism.

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute leukaemia	DISDQFDI	Strong	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[1]
B-cell acute lymphoblastic leukaemia	DISKLOKC	Strong	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[2]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[3]
Lymphoid leukemia	DIS65TYQ	Strong	Altered Expression	[1]
Obesity	DIS47Y1K	Strong	Genetic Variation	[4]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Altered Expression	[1]
Ventricular tachycardia	DISIBXJ3	Strong	Genetic Variation	[5]
Wilms tumor	DISB6T16	Strong	Altered Expression	[6]
Neoplasm	DISZKGEW	Limited	Altered Expression	[7]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[8]
Pulmonary disease	DIS6060I	Limited	Biomarker	[9]

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-3 (IRX3).	[10]

23 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 Iroquois-class homeodomain protein IRX-3 (IRX3).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Iroquois-class homeodomain protein IRX-3 (IRX3).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Iroquois-class homeodomain protein IRX-3 (IRX3).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Iroquois-class homeodomain protein IRX-3 (IRX3).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Iroquois-class homeodomain protein IRX-3 (IRX3).	[15]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Iroquois-class homeodomain protein IRX-3 (IRX3).	[16]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Iroquois-class homeodomain protein IRX-3 (IRX3).	[17]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Iroquois-class homeodomain protein IRX-3 (IRX3).	[18]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Iroquois-class homeodomain protein IRX-3 (IRX3).	[19]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Iroquois-class homeodomain protein IRX-3 (IRX3).	[20]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Iroquois-class homeodomain protein IRX-3 (IRX3).	[21]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Iroquois-class homeodomain protein IRX-3 (IRX3).	[22]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Iroquois-class homeodomain protein IRX-3 (IRX3).	[15]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Iroquois-class homeodomain protein IRX-3 (IRX3).	[23]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Iroquois-class homeodomain protein IRX-3 (IRX3).	[24]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Iroquois-class homeodomain protein IRX-3 (IRX3).	[25]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Iroquois-class homeodomain protein IRX-3 (IRX3).	[26]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Iroquois-class homeodomain protein IRX-3 (IRX3).	[27]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Iroquois-class homeodomain protein IRX-3 (IRX3).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Iroquois-class homeodomain protein IRX-3 (IRX3).	[28]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Iroquois-class homeodomain protein IRX-3 (IRX3).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Iroquois-class homeodomain protein IRX-3 (IRX3).	[30]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Iroquois-class homeodomain protein IRX-3 (IRX3).	[31]

References

• [1] Derepression of the Iroquois Homeodomain Transcription Factor Gene IRX3 Confers Differentiation Block in Acute Leukemia.Cell Rep. 2018 Jan 16;22(3):638-652. doi: 10.1016/j.celrep.2017.12.063.
• [2] FTO Gene Affects Obesity and Breast Cancer Through Similar Mechanisms: A New Insight into the Molecular Therapeutic Targets.Nutr Cancer. 2018 Jan;70(1):30-36. doi: 10.1080/01635581.2018.1397709. Epub 2017 Dec 8.
• [3] Downregulation of miR-377 contributes to IRX3 deregulation in hepatocellular carcinoma.Oncol Rep. 2016 Jul;36(1):247-52. doi: 10.3892/or.2016.4815. Epub 2016 May 18.
• [4] The role of the genetic variants IRX3 rs3751723 and FTO rs9939609 in the obesity phenotypes of children and adolescents.Obes Res Clin Pract. 2019 Mar-Apr;13(2):137-142. doi: 10.1016/j.orcp.2019.01.005. Epub 2019 Jan 31.
• [5] A genome-wide search for common SNP x SNP interactions on the risk of venous thrombosis.BMC Med Genet. 2013 Mar 20;14:36. doi: 10.1186/1471-2350-14-36.
• [6] 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.
• [7] Deletions of 16q in Wilms tumors localize to blastemal-anaplastic cells and are associated with reduced expression of the IRXB renal tubulogenesis gene cluster.Am J Pathol. 2010 Nov;177(5):2609-21. doi: 10.2353/ajpath.2010.100130. Epub 2010 Sep 16.
• [8] Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX, SOX4, and IRX3.Proc Natl Acad Sci U S A. 2010 Jan 12;107(2):775-80. doi: 10.1073/pnas.0911591107. Epub 2009 Dec 22.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity. Blood. 2007 May 15;109(10):4450-60.
• [13] 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.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [16] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [17] 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.
• [18] 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.
• [19] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [20] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [21] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [22] 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.
• [23] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [24] 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.
• [25] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [26] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [27] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [28] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [29] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [30] 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.
• [31] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.