Details of Drug Off-Target (DOT)

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

• DOT Name: Homeobox protein Nkx-2.2 (NKX2-2)
• Synonyms: Homeobox protein NK-2 homolog B
• Gene Name: NKX2-2
• Related Disease:
  Astrocytoma
  Classic Hodgkin lymphoma
  Ewing sarcoma
  Malignant soft tissue neoplasm
  Metastatic malignant neoplasm
  Neonatal diabetes mellitus
  Sarcoma
  Soft tissue neoplasm
  Bone osteosarcoma
  Neuroblastoma
  Osteosarcoma
• UniProt ID: NKX22_HUMAN
• Pfam ID: PF00046
• Sequence:
  MSLTNTKTGFSVKDILDLPDTNDEEGSVAEGPEEENEGPEPAKRAGPLGQGALDAVQSLP
  LKNPFYDSSDNPYTRWLASTEGLQYSLHGLAAGAPPQDSSSKSPEPSADESPDNDKETPG
  GGGDAGKKRKRRVLFSKAQTYELERRFRQQRYLSAPEREHLASLIRLTPTQVKIWFQNHR
  YKMKRARAEKGMEVTPLPSPRRVAVPVLVRDGKPCHALKAQDLAAATFQAGIPFSAYSAQ
  SLQHMQYNAQYSSASTPQYPTAHPLVQAQQWTW
• Function: Transcriptional activator involved in the development of insulin-producting beta cells in the endocrine pancreas. May also be involved in specifying diencephalic neuromeric boundaries, and in controlling the expression of genes that play a role in axonal guidance. Binds to elements within the NEUROD1 promoter.
• KEGG Pathway: Maturity onset diabetes of the young (hsa04950)
• Reactome Pathway:
  Regulation of gene expression in endocrine-committed (NEUROG3+) progenitor cells (R-HSA-210746)
  Regulation of gene expression in beta cells (R-HSA-210745)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Astrocytoma	DISL3V18	Strong	Biomarker	[1]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Altered Expression	[2]
Ewing sarcoma	DISQYLV3	Strong	Altered Expression	[3]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Altered Expression	[4]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[5]
Neonatal diabetes mellitus	DISFHF9K	Strong	Autosomal recessive	[6]
Sarcoma	DISZDG3U	Strong	Altered Expression	[4]
Soft tissue neoplasm	DISP2OHE	Strong	Biomarker	[7]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[8]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[9]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Homeobox protein Nkx-2.2 (NKX2-2).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Homeobox protein Nkx-2.2 (NKX2-2).	[12]

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-2.2 (NKX2-2).	[11]

References

• [1] Expression of oligodendroglial and astrocytic lineage markers in diffuse gliomas: use of YKL-40, ApoE, ASCL1, and NKX2-2.J Neuropathol Exp Neurol. 2006 Dec;65(12):1149-56. doi: 10.1097/01.jnen.0000248543.90304.2b.
• [2] NKL homeobox gene NKX2-2 is aberrantly expressed in Hodgkin lymphoma.Oncotarget. 2018 Dec 25;9(101):37480-37496. doi: 10.18632/oncotarget.26459. eCollection 2018 Dec 25.
• [3] Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility.Nat Commun. 2018 Aug 9;9(1):3184. doi: 10.1038/s41467-018-05537-2.
• [4] PAX7 immunohistochemical evaluation of Ewing sarcoma and other small round cell tumours.Histopathology. 2018 Oct;73(4):645-652. doi: 10.1111/his.13689. Epub 2018 Aug 2.
• [5] Novel markers of subclinical disease for Ewing family tumors from gene expression profiling.Clin Cancer Res. 2007 Dec 1;13(23):6978-83. doi: 10.1158/1078-0432.CCR-07-1417.
• [6] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [7] Evaluation of NKX2-2 expression in round cell sarcomas and other tumors with EWSR1 rearrangement: imperfect specificity for Ewing sarcoma.Mod Pathol. 2016 Apr;29(4):370-80. doi: 10.1038/modpathol.2016.31. Epub 2016 Feb 5.
• [8] NKX2-2 Suppresses Osteosarcoma Metastasis and Proliferation by Downregulating Multiple Target Genes.J Cancer. 2018 Aug 6;9(17):3067-3077. doi: 10.7150/jca.26382. eCollection 2018.
• [9] Expression and epigenetic modulation of sonic hedgehog-GLI1 pathway genes in neuroblastoma cell lines and tumors.Tumour Biol. 2011 Feb;32(1):113-27. doi: 10.1007/s13277-010-0105-x. Epub 2010 Sep 10.
• [10] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [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] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.