Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJBOTD8)

• DOT Name: Protein NDRG4 (NDRG4)
• Synonyms: Brain development-related molecule 1; N-myc downstream-regulated gene 4 protein; Vascular smooth muscle cell-associated protein 8; SMAP-8
• Gene Name: NDRG4
• Related Disease:
  Cerebral infarction
  Glioblastoma multiforme
  Adrenocortical carcinoma
  Aplasia cutis congenita
  Colorectal carcinoma
  Corpus callosum, agenesis of
  Epilepsy
  Gastric cancer
  Glioma
  Infantile myofibromatosis
  Inflammatory bowel disease
  Malignant tumor of adrenal cortex
  Meningioma
  Neoplasm
  Obesity
  Prostate cancer
  Prostate carcinoma
  Schizophrenia
  Stomach cancer
  Adenoma
  Advanced cancer
• UniProt ID: NDRG4_HUMAN
• Pfam ID: PF03096
• Sequence:
  MPECWDGEHDIETPYGLLHVVIRGSPKGNRPAILTYHDVGLNHKLCFNTFFNFEDMQEIT
  KHFVVCHVDAPGQQVGASQFPQGYQFPSMEQLAAMLPSVVQHFGFKYVIGIGVGAGAYVL
  AKFALIFPDLVEGLVLVNIDPNGKGWIDWAATKLSGLTSTLPDTVLSHLFSQEELVNNTE
  LVQSYRQQIGNVVNQANLQLFWNMYNSRRDLDINRPGTVPNAKTLRCPVMLVVGDNAPAE
  DGVVECNSKLDPTTTTFLKMADSGGLPQVTQPGKLTEAFKYFLQGMGYIAYLKDRRLSGG
  AVPSASMTRLARSRTASLTSASSVDGSRPQACTHSESSEGLGQVNHTMEVSC
• Function: Contributes to the maintenance of intracerebral BDNF levels within the normal range, which is necessary for the preservation of spatial learning and the resistance to neuronal cell death caused by ischemic stress. May enhance growth factor-induced ERK1 and ERK2 phosphorylation, including that induced by PDGF and FGF. May attenuate NGF-promoted ELK1 phosphorylation in a microtubule-dependent manner.
• Tissue Specificity: Expressed predominantly in brain and heart (at protein level). In the brain, detected in astrocytes. Isoform 1 and isoform 2 are only expressed in brain. Isoform 3 is expressed in both heart and brain. Up-regulated in glioblastoma multiforme cells.

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cerebral infarction	DISR1WNP	Definitive	Biomarker	[1]
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[2]
Adrenocortical carcinoma	DISZF4HX	Strong	Altered Expression	[3]
Aplasia cutis congenita	DISMDAYM	Strong	Altered Expression	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Corpus callosum, agenesis of	DISO9P40	Strong	Altered Expression	[3]
Epilepsy	DISBB28L	Strong	Biomarker	[5]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[6]
Glioma	DIS5RPEH	Strong	Biomarker	[7]
Infantile myofibromatosis	DISXT8Z7	Strong	Genetic Variation	[8]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[9]
Malignant tumor of adrenal cortex	DIS7E0I8	Strong	Altered Expression	[3]
Meningioma	DISPT4TG	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Obesity	DIS47Y1K	Strong	Altered Expression	[10]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[11]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[11]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[12]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[6]
Adenoma	DIS78ZEV	Limited	Biomarker	[4]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Protein NDRG4 (NDRG4).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein NDRG4 (NDRG4).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protein NDRG4 (NDRG4).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein NDRG4 (NDRG4).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein NDRG4 (NDRG4).	[17]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Protein NDRG4 (NDRG4).	[18]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Protein NDRG4 (NDRG4).	[19]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Protein NDRG4 (NDRG4).	[20]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Protein NDRG4 (NDRG4).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Protein NDRG4 (NDRG4).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein NDRG4 (NDRG4).	[23]

References

• [1] NDRG4 protein-deficient mice exhibit spatial learning deficits and vulnerabilities to cerebral ischemia.J Biol Chem. 2011 Jul 22;286(29):26158-65. doi: 10.1074/jbc.M111.256446. Epub 2011 Jun 2.
• [2] NDRG2 and NDRG4 Expression Is Altered in Glioblastoma and Influences Survival in Patients with MGMT-methylated Tumors.Anticancer Res. 2016 Mar;36(3):887-97.
• [3] MiR-483-5p and miR-139-5p promote aggressiveness by targeting N-myc downstream-regulated gene family members in adrenocortical cancer.Int J Cancer. 2018 Aug 15;143(4):944-957. doi: 10.1002/ijc.31363. Epub 2018 Mar 30.
• [4] A systematic review and quantitative assessment of methylation biomarkers in fecal DNA and colorectal cancer and its precursor, colorectal adenoma.Mutat Res Rev Mutat Res. 2019 Jan-Mar;779:45-57. doi: 10.1016/j.mrrev.2019.01.003. Epub 2019 Jan 16.
• [5] Fold prediction and comparative modeling of Bdm1: a probable alpha/beta hydrolase associated with hot water epilepsy.J Mol Model. 2003 Feb;9(1):3-8. doi: 10.1007/s00894-002-0102-0. Epub 2003 Jan 17.
• [6] NDRG4 in gastric cancer determines tumor cell proliferation and clinical outcome.Mol Carcinog. 2018 Jun;57(6):762-771. doi: 10.1002/mc.22798. Epub 2018 Mar 24.
• [7] Nervous NDRGs: the N-myc downstream-regulated gene family in the central and peripheral nervous system.Neurogenetics. 2019 Oct;20(4):173-186. doi: 10.1007/s10048-019-00587-0. Epub 2019 Sep 4.
• [8] Exome sequencing identifies a novel homozygous variant in NDRG4 in a family with infantile myofibromatosis.Eur J Med Genet. 2014 Nov-Dec;57(11-12):643-8. doi: 10.1016/j.ejmg.2014.08.010. Epub 2014 Sep 18.
• [9] Stool DNA testing for the detection of colorectal neoplasia in patients with inflammatory bowel disease.Aliment Pharmacol Ther. 2013 Mar;37(5):546-54. doi: 10.1111/apt.12218. Epub 2013 Jan 24.
• [10] NDRG4 stratifies the prognostic value of body mass index in colorectal cancer.Oncotarget. 2016 Jan 12;7(2):1311-22. doi: 10.18632/oncotarget.6182.
• [11] 6-gene promoter methylation assay is potentially applicable for prostate cancer clinical staging based on urine collection following prostatic massage.Oncol Lett. 2019 Dec;18(6):6917-6925. doi: 10.3892/ol.2019.11015. Epub 2019 Oct 29.
• [12] Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection.Nat Genet. 2018 Mar;50(3):381-389. doi: 10.1038/s41588-018-0059-2. Epub 2018 Feb 26.
• [13] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [14] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [15] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [16] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [17] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [18] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [19] 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.
• [20] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [21] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [22] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [23] 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.