Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF4IL5J)

• DOT Name: Homeobox protein Nkx-2.3 (NKX2-3)
• Synonyms: Homeobox protein NK-2 homolog C
• Gene Name: NKX2-3
• Related Disease:
  Coeliac disease
  Irritable bowel syndrome
  T-cell acute lymphoblastic leukaemia
  Ulcerative colitis
  Inflammatory bowel disease
  leukaemia
  Leukemia
  Neuroendocrine cancer
  Advanced cancer
  Colorectal carcinoma
  Lymphoma
  Neoplasm
• UniProt ID: NKX23_HUMAN
• Pfam ID: PF00046
• Sequence:
  MMLPSPVTSTPFSVKDILNLEQQHQHFHGAHLQADLEHHFHSAPCMLAAAEGTQFSDGGE
  EDEEDEGEKLSYLNSLAAADGHGDSGLCPQGYVHTVLRDSCSEPKEHEEEPEVVRDRSQK
  SCQLKKSLETAGDCKAAEESERPKPRSRRKPRVLFSQAQVFELERRFKQQRYLSAPEREH
  LASSLKLTSTQVKIWFQNRRYKCKRQRQDKSLELGAHAPPPPPRRVAVPVLVRDGKPCVT
  PSAQAYGAPYSVGASAYSYNSFPAYGYGNSAAAAAAAAAAAAAAAAYSSSYGCAYPAGGG
  GGGGGTSAATTAMQPACSAAGGGPFVNVSNLGGFGSGGSAQPLHQGTAAGAACAQGTLQG
  IRAW
• Function: Transcription factor.

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Coeliac disease	DISIY60C	Strong	Genetic Variation	[1]
Irritable bowel syndrome	DIS27206	Strong	Genetic Variation	[2]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Genetic Variation	[3]
Ulcerative colitis	DIS8K27O	Strong	Genetic Variation	[4]
Inflammatory bowel disease	DISGN23E	moderate	Altered Expression	[5]
leukaemia	DISS7D1V	moderate	Biomarker	[6]
Leukemia	DISNAKFL	moderate	Biomarker	[6]
Neuroendocrine cancer	DISVGJET	moderate	Altered Expression	[7]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[8]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[9]
Lymphoma	DISN6V4S	Limited	Altered Expression	[8]
Neoplasm	DISZKGEW	Limited	Altered Expression	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Homeobox protein Nkx-2.3 (NKX2-3).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Homeobox protein Nkx-2.3 (NKX2-3).	[11]

2 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 decreases the methylation of Homeobox protein Nkx-2.3 (NKX2-3).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Homeobox protein Nkx-2.3 (NKX2-3).	[13]

References

• [1] Lack of association of NKX2-3, IRGM, and ATG16L1 inflammatory bowel disease susceptibility variants with celiac disease.Hum Immunol. 2009 Nov;70(11):946-9. doi: 10.1016/j.humimm.2009.08.004. Epub 2009 Aug 13.
• [2] NKX2-3 variant rs11190140 is associated with IBD and alters binding of NFAT.Mol Genet Metab. 2011 Sep-Oct;104(1-2):174-9. doi: 10.1016/j.ymgme.2011.06.023. Epub 2011 Jul 6.
• [3] TCR rearrangements identify a subgroup of NKL-deregulated adult T-ALLs associated with favorable outcome.Leukemia. 2018 Jan;32(1):61-71. doi: 10.1038/leu.2017.176. Epub 2017 Jun 8.
• [4] Characteristics of Japanese inflammatory bowel disease susceptibility loci.J Gastroenterol. 2014 Aug;49(8):1217-30. doi: 10.1007/s00535-013-0866-2. Epub 2013 Aug 13.
• [5] Differential Effects of the Absence of Nkx2-3 and MAdCAM-1 on the Distribution of Intestinal Type 3 Innate Lymphoid Cells and Postnatal SILT Formation in Mice.Front Immunol. 2019 Mar 5;10:366. doi: 10.3389/fimmu.2019.00366. eCollection 2019.
• [6] Unique long non-coding RNA expression signature in ETV6/RUNX1-driven B-cell precursor acute lymphoblastic leukemia.Oncotarget. 2016 Nov 8;7(45):73769-73780. doi: 10.18632/oncotarget.12063.
• [7] Novel markers for enterochromaffin cells and gastrointestinal neuroendocrine carcinomas.Mod Pathol. 2009 Feb;22(2):261-72. doi: 10.1038/modpathol.2008.174. Epub 2008 Oct 24.
• [8] Homeobox NKX2-3 promotes marginal-zone lymphomagenesis by activating B-cell receptor signalling and shaping lymphocyte dynamics.Nat Commun. 2016 Jun 14;7:11889. doi: 10.1038/ncomms11889.
• [9] Genes regulated by Nkx2-3 in sporadic and inflammatory bowel disease-associated colorectal cancer cell lines.Dig Dis Sci. 2010 Nov;55(11):3171-80. doi: 10.1007/s10620-010-1138-0. Epub 2010 Feb 18.
• [10] 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.
• [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] 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.
• [13] 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.