Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBHXXQ2)

• DOT Name: Iroquois-class homeodomain protein IRX-2 (IRX2)
• Synonyms: Homeodomain protein IRXA2; Iroquois homeobox protein 2
• Gene Name: IRX2
• Related Disease:
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Bone osteosarcoma
  Epithelial neoplasm
  Malignant peripheral nerve sheath tumor
  Osteosarcoma
  Sarcoma
  Soft tissue sarcoma
  Neoplasm
  Advanced cancer
  Pulmonary disease
• UniProt ID: IRX2_HUMAN
• Pfam ID: PF05920
• Sequence:
  MSYPQGYLYQAPGSLALYSCPAYGASALAAPRSEELARSASGSAFSPYPGSAAFTAQAAT
  GFGSPLQYSADAAAAAAGFPSYMGAPYDAHTTGMTGAISYHPYGSAAYPYQLNDPAYRKN
  ATRDATATLKAWLNEHRKNPYPTKGEKIMLAIITKMTLTQVSTWFANARRRLKKENKMTW
  APRNKSEDEDEDEGDATRSKDESPDKAQEGTETSAEDEGISLHVDSLTDHSCSAESDGEK
  LPCRAGDPLCESGSECKDKYDDLEDDEDDDEEGERGLAPPKPVTSSPLTGLEAPLLSPPP
  EAAPRGGRKTPQGSRTSPGAPPPASKPKLWSLAEIATSDLKQPSLGPGCGPPGLPAAAAP
  ASTGAPPGGSPYPASPLLGRPLYYTSPFYGNYTNYGNLNAALQGQGLLRYNSAAAAPGEA
  LHTAPKAASDAGKAGAHPLESHYRSPGGGYEPKKDASEGCTVVGGGVQPYL

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Definitive	Altered Expression	[1]
Breast neoplasm	DISNGJLM	Definitive	Altered Expression	[1]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[2]
Epithelial neoplasm	DIS0T594	Strong	Genetic Variation	[3]
Malignant peripheral nerve sheath tumor	DIS0JTN6	Strong	Biomarker	[4]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[2]
Sarcoma	DISZDG3U	Strong	Biomarker	[4]
Soft tissue sarcoma	DISSN8XB	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Disputed	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[5]
Pulmonary disease	DIS6060I	Limited	Biomarker	[6]

2 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-2 (IRX2).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Iroquois-class homeodomain protein IRX-2 (IRX2).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Iroquois-class homeodomain protein IRX-2 (IRX2).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Iroquois-class homeodomain protein IRX-2 (IRX2).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Iroquois-class homeodomain protein IRX-2 (IRX2).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Iroquois-class homeodomain protein IRX-2 (IRX2).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Iroquois-class homeodomain protein IRX-2 (IRX2).	[12]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Iroquois-class homeodomain protein IRX-2 (IRX2).	[13]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Iroquois-class homeodomain protein IRX-2 (IRX2).	[14]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Iroquois-class homeodomain protein IRX-2 (IRX2).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Iroquois-class homeodomain protein IRX-2 (IRX2).	[11]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Iroquois-class homeodomain protein IRX-2 (IRX2).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Iroquois-class homeodomain protein IRX-2 (IRX2).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Iroquois-class homeodomain protein IRX-2 (IRX2).	[17]

References

• [1] Iroquois homeobox 2 suppresses cellular motility and chemokine expression in breast cancer cells.BMC Cancer. 2015 Nov 11;15:896. doi: 10.1186/s12885-015-1907-4.
• [2] IRX2-mediated upregulation of MMP-9 and VEGF in a PI3K/AKT-dependent manner.Mol Med Rep. 2015 Sep;12(3):4346-4351. doi: 10.3892/mmr.2015.3915. Epub 2015 Jun 11.
• [3] Increased immune infiltration and chemokine receptor expression in head and neck epithelial tumors after neoadjuvant immunotherapy with the IRX-2 regimen.Oncoimmunology. 2018 Feb 21;7(5):e1423173. doi: 10.1080/2162402X.2017.1423173. eCollection 2018.
• [4] Frequent amplifications and abundant expression of TRIO, NKD2, and IRX2 in soft tissue sarcomas.Genes Chromosomes Cancer. 2006 Sep;45(9):829-38. doi: 10.1002/gcc.20343.
• [5] A Phase Ib Study of Preoperative, Locoregional IRX-2 Cytokine Immunotherapy to Prime Immune Responses in Patients with Early-Stage Breast Cancer.Clin Cancer Res. 2020 Apr 1;26(7):1595-1605. doi: 10.1158/1078-0432.CCR-19-1119. Epub 2019 Dec 12.
• [6] 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.
• [7] 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.
• [8] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [9] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [10] Transcriptional responses to estrogen and progesterone in mammary gland identify networks regulating p53 activity. Endocrinology. 2008 Oct;149(10):4809-20. doi: 10.1210/en.2008-0035. Epub 2008 Jun 12.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [15] 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.
• [16] Transcriptomic?pathway?and?benchmark dose analysis of Bisphenol A, Bisphenol S, Bisphenol F, and 3,3',5,5'-Tetrabromobisphenol A in H9 human embryonic stem cells. Toxicol In Vitro. 2021 Apr;72:105097. doi: 10.1016/j.tiv.2021.105097. Epub 2021 Jan 18.
• [17] 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.