Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH4NRH7)

• DOT Name: Homeobox protein Nkx-3.2 (NKX3-2)
• Synonyms: Bagpipe homeobox protein homolog 1; Homeobox protein NK-3 homolog B
• Gene Name: NKX3-2
• Related Disease:
  Spondylo-megaepiphyseal-metaphyseal dysplasia
  Advanced cancer
  T-cell acute lymphoblastic leukaemia
  Gastric cancer
  Osteochondrodysplasia
  Skeletal dysplasia
  Stomach cancer
• UniProt ID: NKX32_HUMAN
• Pfam ID: PF00046
• Sequence:
  MAVRGANTLTSFSIQAILNKKEERGGLAAPEGRPAPGGTAASVAAAPAVCCWRLFGERDA
  GALGGAEDSLLASPAGTRTAAGRTAESPEGWDSDSALSEENESRRRCADARGASGAGLAG
  GSLSLGQPVCELAASKDLEEEAAGRSDSEMSASVSGDRSPRTEDDGVGPRGAHVSALCSG
  AGGGGGSGPAGVAEEEEEPAAPKPRKKRSRAAFSHAQVFELERRFNHQRYLSGPERADLA
  ASLKLTETQVKIWFQNRRYKTKRRQMAADLLASAPAAKKVAVKVLVRDDQRQYLPGEVLR
  PPSLLPLQPSYYYPYYCLPGWALSTCAAAAGTQ
• Function: Transcriptional repressor that acts as a negative regulator of chondrocyte maturation. PLays a role in distal stomach development; required for proper antral-pyloric morphogenesis and development of antral-type epithelium. In concert with GSC, defines the structural components of the middle ear; required for tympanic ring and gonium development and in the regulation of the width of the malleus.
• Tissue Specificity: Expressed at highest levels in cartilage, bone (osteosarcoma) and gut (small intestine and colon), whereas moderate expression is seen in trachea and brain. Expressed in visceral mesoderm and embryonic skeleton.
• Reactome Pathway: Regulation of RUNX2 expression and activity (R-HSA-8939902)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Spondylo-megaepiphyseal-metaphyseal dysplasia	DISBBAGE	Definitive	Autosomal recessive	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Altered Expression	[2]
Gastric cancer	DISXGOUK	moderate	Biomarker	[3]
Osteochondrodysplasia	DIS9SPWW	moderate	Biomarker	[4]
Skeletal dysplasia	DIS5Z8U6	moderate	Biomarker	[4]
Stomach cancer	DISKIJSX	moderate	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Homeobox protein Nkx-3.2 (NKX3-2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Homeobox protein Nkx-3.2 (NKX3-2).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Homeobox protein Nkx-3.2 (NKX3-2).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Homeobox protein Nkx-3.2 (NKX3-2).	[8]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Homeobox protein Nkx-3.2 (NKX3-2).	[9]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Homeobox protein Nkx-3.2 (NKX3-2).	[10]
GSK2816126	DMJDVW4	Phase 1	GSK2816126 increases the expression of Homeobox protein Nkx-3.2 (NKX3-2).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Homeobox protein Nkx-3.2 (NKX3-2).	[13]

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 Homeobox protein Nkx-3.2 (NKX3-2).	[11]

References

• [1] 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.
• [2] Aberrant activity of NKL homeobox gene NKX3-2 in a T-ALL subset.PLoS One. 2018 May 10;13(5):e0197194. doi: 10.1371/journal.pone.0197194. eCollection 2018.
• [3] Bapx1 mediates transforming growth factor-- induced epithelial-mesenchymal transition and promotes a malignancy phenotype of gastric cancer cells.Biochem Biophys Res Commun. 2017 Apr 29;486(2):285-292. doi: 10.1016/j.bbrc.2017.03.029. Epub 2017 Mar 14.
• [4] Sequence and chromosomal assignment of human BAPX1, a bagpipe-related gene, to 4p16.1: a candidate gene for skeletal dysplasia.Genomics. 1997 Oct 15;45(2):425-8. doi: 10.1006/geno.1997.4926.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [8] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [11] 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.
• [12] Epigenetic control of skeletal development by the histone methyltransferase Ezh2. J Biol Chem. 2015 Nov 13;290(46):27604-17.
• [13] 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.