Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOB8366)

• DOT Name: Serine/threonine-protein kinase Nek4 (NEK4)
• Synonyms: EC 2.7.11.1; Never in mitosis A-related kinase 4; NimA-related protein kinase 4; Serine/threonine-protein kinase 2; Serine/threonine-protein kinase NRK2
• Gene Name: NEK4
• Related Disease:
  Non-small-cell lung cancer
  Bipolar disorder
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Lung cancer
  Lung carcinoma
  Major depressive disorder
  Schizophrenia
• UniProt ID: NEK4_HUMAN
• EC Number: 2.7.11.1
• Pfam ID: PF00069
• Sequence:
  MPLAAYCYLRVVGKGSYGEVTLVKHRRDGKQYVIKKLNLRNASSRERRAAEQEAQLLSQL
  KHPNIVTYKESWEGGDGLLYIVMGFCEGGDLYRKLKEQKGQLLPENQVVEWFVQIAMALQ
  YLHEKHILHRDLKTQNVFLTRTNIIKVGDLGIARVLENHCDMASTLIGTPYYMSPELFSN
  KPYNYKSDVWALGCCVYEMATLKHAFNAKDMNSLVYRIIEGKLPPMPRDYSPELAELIRT
  MLSKRPEERPSVRSILRQPYIKRQISFFLEATKIKTSKNNIKNGDSQSKPFATVVSGEAE
  SNHEVIHPQPLSSEGSQTYIMGEGKCLSQEKPRASGLLKSPASLKAHTCKQDLSNTTELA
  TISSVNIDILPAKGRDSVSDGFVQENQPRYLDASNELGGICSISQVEEEMLQDNTKSSAQ
  PENLIPMWSSDIVTGEKNEPVKPLQPLIKEQKPKDQSLALSPKLECSGTILAHSNLRLLG
  SSDSPASASRVAGITGVCHHAQDQVAGECIIEKQGRIHPDLQPHNSGSEPSLSRQRRQKR
  REQTEHRGEKRQVRRDLFAFQESPPRFLPSHPIVGKVDVTSTQKEAENQRRVVTGSVSSS
  RSSEMSSSKDRPLSARERRRLKQSQEEMSSSGPSVRKASLSVAGPGKPQEEDQPLPARRL
  SSDCSVTQERKQIHCLSEDELSSSTSSTDKSDGDYGEGKGQTNEINALVQLMTQTLKLDS
  KESCEDVPVANPVSEFKLHRKYRDTLILHGKVAEEAEEIHFKELPSAIMPGSEKIRRLVE
  VLRTDVIRGLGVQLLEQVYDLLEEEDEFDREVRLREHMGEKYTTYSVKARQLKFFEENMN
  F
• Function: Protein kinase that seems to act exclusively upon threonine residues. Required for normal entry into proliferative arrest after a limited number of cell divisions, also called replicative senescence. Required for normal cell cycle arrest in response to double-stranded DNA damage.
• Tissue Specificity: Highest expression in adult heart, followed by pancreas, skeletal muscle, brain, testis, retina, liver, kidney, lung and placenta. Present in most primary carcinomas.

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-small-cell lung cancer	DIS5Y6R9	Definitive	Genetic Variation	[1]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[2]
Colon cancer	DISVC52G	Strong	Biomarker	[3]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[4]
Lung cancer	DISCM4YA	Strong	Biomarker	[5]
Lung carcinoma	DISTR26C	Strong	Biomarker	[5]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[6]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[7]

9 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 Serine/threonine-protein kinase Nek4 (NEK4).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Serine/threonine-protein kinase Nek4 (NEK4).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Serine/threonine-protein kinase Nek4 (NEK4).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Serine/threonine-protein kinase Nek4 (NEK4).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Serine/threonine-protein kinase Nek4 (NEK4).	[12]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Serine/threonine-protein kinase Nek4 (NEK4).	[13]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Serine/threonine-protein kinase Nek4 (NEK4).	[15]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Serine/threonine-protein kinase Nek4 (NEK4).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Serine/threonine-protein kinase Nek4 (NEK4).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Serine/threonine-protein kinase Nek4 (NEK4).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Serine/threonine-protein kinase Nek4 (NEK4).	[17]

References

• [1] Nek4 status differentially alters sensitivity to distinct microtubule poisons.Cancer Res. 2010 Feb 1;70(3):1033-41. doi: 10.1158/0008-5472.CAN-09-2113. Epub 2010 Jan 26.
• [2] Investigation of manic and euthymic episodes identifies state- and trait-specific gene expression and STAB1 as a new candidate gene for bipolar disorder.Transl Psychiatry. 2014 Aug 19;4(8):e426. doi: 10.1038/tp.2014.71.
• [3] Possible role of nuclear -catenin in resistance to preoperative chemoradiotherapy in locally advanced rectal cancer.Histopathology. 2017 Aug;71(2):227-237. doi: 10.1111/his.13227. Epub 2017 May 22.
• [4] Colorectal cancer stages transcriptome analysis.PLoS One. 2017 Nov 28;12(11):e0188697. doi: 10.1371/journal.pone.0188697. eCollection 2017.
• [5] NEK4 kinase regulates EMT to promote lung cancer metastasis.J Cell Mol Med. 2018 Dec;22(12):5877-5887. doi: 10.1111/jcmm.13857. Epub 2018 Sep 24.
• [6] A mega-analysis of genome-wide association studies for major depressive disorder.Mol Psychiatry. 2013 Apr;18(4):497-511. doi: 10.1038/mp.2012.21. Epub 2012 Apr 3.
• [7] The genome-wide risk alleles for psychiatric disorders at 3p21.1 show convergent effects on mRNA expression, cognitive function, and mushroom dendritic spine.Mol Psychiatry. 2020 Jan;25(1):48-66. doi: 10.1038/s41380-019-0592-0. Epub 2019 Nov 13.
• [8] 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.
• [9] 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.
• [10] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [11] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [14] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [15] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [16] Cellular response to 5-fluorouracil (5-FU) in 5-FU-resistant colon cancer cell lines during treatment and recovery. Mol Cancer. 2006 May 18;5:20. doi: 10.1186/1476-4598-5-20.
• [17] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [18] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.