Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMYHUV2)

• DOT Name: Notch-regulated ankyrin repeat-containing protein (NRARP)
• Gene Name: NRARP
• Related Disease:
  Acute otitis media
  Advanced cancer
  Brain cancer
  Brain neoplasm
  leukaemia
  Leukemia
  Neoplasm
  Non-small-cell lung cancer
  T-cell acute lymphoblastic leukaemia
  Thyroid gland carcinoma
  Breast cancer
  Breast carcinoma
  Thyroid cancer
  Thyroid gland papillary carcinoma
  Thyroid tumor
• UniProt ID: NRARP_HUMAN
• PDB ID: 6PY8
• Pfam ID: PF12796
• Sequence:
  MSQAELSTCSAPQTQRIFQEAVRKGNTQELQSLLQNMTNCEFNVNSFGPEGQTALHQSVI
  DGNLELVKLLVKFGADIRLANRDGWSALHIAAFGGHQDIVLYLITKAKYAASGR
• Function: Downstream effector of Notch signaling. Involved in the regulation of liver cancer cells self-renewal. Involved in angiogenesis acting downstream of Notch at branch points to regulate vascular density. Proposed to integrate endothelial Notch and Wnt signaling to control stalk cell proliferation and to stablilize new endothelial connections during angiogenesis. During somitogenesis involved in maintenance of proper somite segmentation and proper numbers of somites and vertebrae. Required for proper anterior-posterior somite patterning. Proposed to function in a negative feedback loop to destabilize Notch 1 intracellular domain (NICD) and down-regulate the Notch signal, preventing expansion of the Notch signal into the anterior somite domain.
• KEGG Pathway: Notch sig.ling pathway (hsa04330)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute otitis media	DISL8D8G	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Brain cancer	DISBKFB7	Strong	Biomarker	[3]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[3]
leukaemia	DISS7D1V	Strong	Biomarker	[4]
Leukemia	DISNAKFL	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[2]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Biomarker	[4]
Thyroid gland carcinoma	DISMNGZ0	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Limited	Biomarker	[6]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[6]
Thyroid cancer	DIS3VLDH	Limited	Biomarker	[7]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Biomarker	[5]
Thyroid tumor	DISLVKMD	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Notch-regulated ankyrin repeat-containing protein (NRARP).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Notch-regulated ankyrin repeat-containing protein (NRARP).	[9]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Notch-regulated ankyrin repeat-containing protein (NRARP).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Notch-regulated ankyrin repeat-containing protein (NRARP).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Notch-regulated ankyrin repeat-containing protein (NRARP).	[12]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Notch-regulated ankyrin repeat-containing protein (NRARP).	[13]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Notch-regulated ankyrin repeat-containing protein (NRARP).	[14]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Notch-regulated ankyrin repeat-containing protein (NRARP).	[15]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Notch-regulated ankyrin repeat-containing protein (NRARP).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Notch-regulated ankyrin repeat-containing protein (NRARP).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Notch-regulated ankyrin repeat-containing protein (NRARP).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Notch-regulated ankyrin repeat-containing protein (NRARP).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Notch-regulated ankyrin repeat-containing protein (NRARP).	[19]

References

• [1] The Role of the Notch Signal Pathway in Mucosal Cell Metaplasia in Mouse Acute Otitis Media.Sci Rep. 2017 Jul 4;7(1):4588. doi: 10.1038/s41598-017-04639-z.
• [2] Notch-regulated ankyrin-repeat protein is a novel tissue biomarker that predicts poor prognosis in non-small cell lung cancer.Oncol Lett. 2018 Aug;16(2):1885-1891. doi: 10.3892/ol.2018.8826. Epub 2018 May 30.
• [3] Inhibition of notch signaling blocks growth of glioblastoma cell lines and tumor neurospheres.Genes Cancer. 2010 Aug;1(8):822-35. doi: 10.1177/1947601910383564.
• [4] NRARP displays either pro- or anti-tumoral roles in T-cell acute lymphoblastic leukemia depending on Notch and Wnt signaling.Oncogene. 2020 Jan;39(5):975-986. doi: 10.1038/s41388-019-1042-9. Epub 2019 Oct 4.
• [5] Overexpression of NOTCH-regulated Ankyrin Repeat Protein is associated with papillary thyroid carcinoma progression.PLoS One. 2017 Feb 16;12(2):e0167782. doi: 10.1371/journal.pone.0167782. eCollection 2017.
• [6] Overexpression of NOTCH-regulated ankyrin repeat protein is associated with breast cancer cell proliferation.Anticancer Res. 2014 May;34(5):2165-71.
• [7] Downregulation of Notch-regulated Ankyrin Repeat Protein Exerts Antitumor Activities against Growth of Thyroid Cancer.Chin Med J (Engl). 2016 Jul 5;129(13):1544-52. doi: 10.4103/0366-6999.184465.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [10] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [11] 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.
• [12] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [13] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [14] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma. Int J Cancer. 2015 May 1;136(9):2055-64.
• [17] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [18] 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.
• [19] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.