Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL79R2K)

• DOT Name: Iroquois-class homeodomain protein IRX-6 (IRX6)
• Synonyms: Homeodomain protein IRXB3; Iroquois homeobox protein 6
• Gene Name: IRX6
• Related Disease: Hypospadias
• UniProt ID: IRX6_HUMAN
• Pfam ID: PF05920
• Sequence:
  MSFPHFGHPYRGASQFLASASSSTTCCESTQRSVSDVASGSTPAPALCCAPYDSRLLGSA
  RPELGAALGIYGAPYAAAAAAQSYPGYLPYSPEPPSLYGALNPQYEFKEAAGSFTSSLAQ
  PGAYYPYERTLGQYQYERYGAVELSGAGRRKNATRETTSTLKAWLNEHRKNPYPTKGEKI
  MLAIITKMTLTQVSTWFANARRRLKKENKMTWAPKNKGGEERKAEGGEEDSLGCLTADTK
  EVTASQEARGLRLSDLEDLEEEEEEEEEAEDEEVVATAGDRLTEFRKGAQSLPGPCAAAR
  EGRLERRECGLAAPRFSFNDPSGSEEADFLSAETGSPRLTMHYPCLEKPRIWSLAHTATA
  SAVEGAPPARPRPRSPECRMIPGQPPASARRLSVPRDSACDESSCIPKAFGNPKFALQGL
  PLNCAPCPRRSEPVVQCQYPSGAEAG
• Function: Transcription factor. Binds to the iroquois binding site (IBS) motif of target genes to regulate gene expression; functions as a transcriptional activator or repressor. Modulates expression of RCVRN, VSX1, BHLHE22/BHLHB5 and TACR3/Nk3r. Required downstream of retinal bipolar cell specification for the terminal differentiation of type 2, type 3a and possibly type 6 bipolar cells.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypospadias	DIS48CCP	Strong	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Iroquois-class homeodomain protein IRX-6 (IRX6).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Iroquois-class homeodomain protein IRX-6 (IRX6).	[3]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Iroquois-class homeodomain protein IRX-6 (IRX6).	[4]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Iroquois-class homeodomain protein IRX-6 (IRX6).	[3]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Iroquois-class homeodomain protein IRX-6 (IRX6).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Iroquois-class homeodomain protein IRX-6 (IRX6).	[5]

References

• [1] Single Nucleotide Polymorphisms of HAAO and IRX6 Genes as Risk Factors for Hypospadias.J Urol. 2019 Feb;201(2):386-392. doi: 10.1016/j.juro.2018.07.050.
• [2] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] 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.