Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGR01FF)

• DOT Name: Nik-related protein kinase (NRK)
• Synonyms: EC 2.7.11.1
• Gene Name: NRK
• Related Disease:
  Chronic kidney disease
  Hereditary gingival fibromatosis
  Hyperglycemia
  Adult T-cell leukemia/lymphoma
  Cervical Intraepithelial neoplasia
  Nephropathy
  Non-insulin dependent diabetes
  T-cell leukaemia
  Type-1/2 diabetes
  Clear cell renal carcinoma
  Renal cell carcinoma
  Renal fibrosis
  Diabetic kidney disease
  Small lymphocytic lymphoma
  Sotos syndrome
• UniProt ID: NRK_HUMAN
• EC Number: 2.7.11.1
• Pfam ID: PF00780 ; PF00069
• Sequence:
  MAGPGGWRDREVTDLGHLPDPTGIFSLDKTIGLGTYGRIYLGLHEKTGAFTAVKVMNARK
  TPLPEIGRRVRVNKYQKSVGWRYSDEEEDLRTELNLLRKYSFHKNIVSFYGAFFKLSPPG
  QRHQLWMVMELCAAGSVTDVVRMTSNQSLKEDWIAYICREILQGLAHLHAHRVIHRDIKG
  QNVLLTHNAEVKLVDFGVSAQVSRTNGRRNSFIGTPYWMAPEVIDCDEDPRRSYDYRSDV
  WSVGITAIEMAEGAPPLCNLQPLEALFVILRESAPTVKSSGWSRKFHNFMEKCTIKNFLF
  RPTSANMLQHPFVRDIKNERHVVESLTRHLTGIIKKRQKKGIPLIFEREEAIKEQYTVRR
  FRGPSCTHELLRLPTSSRCRPLRVLHGEPSQPRWLPDREEPQVQALQQLQGAARVFMPLQ
  ALDSAPKPLKGQAQAPQRLQGAARVFMPLQAQVKAKASKPLQMQIKAPPRLRRAARVLMP
  LQAQVRAPRLLQVQSQVSKKQQAQTQTSEPQDLDQVPEEFQGQDQVPEQQRQGQAPEQQQ
  RHNQVPEQELEQNQAPEQPEVQEQAAEPAQAETEAEEPESLRVNAQVFLPLLSQDHHVLL
  PLHLDTQVLIPVEGQTEGSPQAQAWTLEPPQAIGSVQALIEGLSRDLLRAPNSNNSKPLG
  PLQTLMENLSSNRFYSQPEQAREKKSKVSTLRQALAKRLSPKRFRAKSSWRPEKLELSDL
  EARRQRRQRRWEDIFNQHEEELRQVDKDKEDESSDNDEVFHSIQAEVQIEPLKPYISNPK
  KIEVQERSPSVPNNQDHAHHVKFSSSVPQRSLLEQAQKPIDIRQRSSQNRQNWLAASESS
  SEEESPVTGRRSQSSPPYSTIDQKLLVDIHVPDGFKVGKISPPVYLTNEWVGYNALSEIF
  RNDWLTPAPVIQPPEEDGDYVELYDASADTDGDDDDESNDTFEDTYDHANGNDDLDNQVD
  QANDVCKDHDDDNNKFVDDVNNNYYEAPSCPRASYGRDGSCKQDGYDGSRGKEEAYRGYG
  SHTANRSHGGSAASEDNAAIGDQEEHAANIGSERRGSEGDGGKGVVRTSEESGALGLNGE
  ENCSETDGPGLKRPASQDFEYLQEEPGGGNEASNAIDSGAAPSAPDHESDNKDISESSTQ
  SDFSANHSSPSKGSGMSADANFASAILYAGFVEVPEESPKQPSEVNVNPLYVSPACKKPL
  IHMYEKEFTSEICCGSLWGVNLLLGTRSNLYLMDRSGKADITKLIRRRPFRQIQVLEPLN
  LLITISGHKNRLRVYHLTWLRNKILNNDPESKRRQEEMLKTEEACKAIDKLTGCEHFSVL
  QHEETTYIAIALKSSIHLYAWAPKSFDESTAIKVCIDQSADSEGDYMSYQAYIRILAKIQ
  AADPVNRFKRPDELLHLLKLKVFPTLDHKPVTVDLAIGSEKRLKIFFSSADGYHLIDAES
  EVMSDVTLPKNPLEIIIPQNIIILPDCLGIGMMLTFNAEALSVEANEQLFKKILEMWKDI
  PSSIAFECTQRTTGWGQKAIEVRSLQSRVLESELKRRSIKKLRFLCTRGDKLFFTSTLRN
  HHSRVYFMTLGKLEELQSNYDV
• Function: May phosphorylate cofilin-1 and induce actin polymerization through this process, during the late stages of embryogenesis. Involved in the TNF-alpha-induced signaling pathway.

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic kidney disease	DISW82R7	Definitive	Biomarker	[1]
Hereditary gingival fibromatosis	DISN1ML3	Definitive	Biomarker	[2]
Hyperglycemia	DIS0BZB5	Definitive	Biomarker	[3]
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Altered Expression	[4]
Cervical Intraepithelial neoplasia	DISXP757	Strong	Biomarker	[5]
Nephropathy	DISXWP4P	Strong	Biomarker	[6]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[7]
T-cell leukaemia	DISJ6YIF	Strong	Altered Expression	[4]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[8]
Clear cell renal carcinoma	DISBXRFJ	moderate	Biomarker	[9]
Renal cell carcinoma	DISQZ2X8	moderate	Biomarker	[9]
Renal fibrosis	DISMHI3I	moderate	Biomarker	[10]
Diabetic kidney disease	DISJMWEY	Disputed	Biomarker	[11]
Small lymphocytic lymphoma	DIS30POX	Limited	Biomarker	[12]
Sotos syndrome	DISN4U1D	Limited	Biomarker	[13]

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 Nik-related protein kinase (NRK).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Nik-related protein kinase (NRK).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Nik-related protein kinase (NRK).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Nik-related protein kinase (NRK).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Nik-related protein kinase (NRK).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Nik-related protein kinase (NRK).	[19]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Nik-related protein kinase (NRK).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Nik-related protein kinase (NRK).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Nik-related protein kinase (NRK).	[22]

References

• [1] Poricoic acid A enhances melatonin inhibition of AKI-to-CKD transition by regulating Gas6/AxlNFB/Nrf2 axis.Free Radic Biol Med. 2019 Apr;134:484-497. doi: 10.1016/j.freeradbiomed.2019.01.046. Epub 2019 Feb 2.
• [2] HGF induces the serinephosphorylation and cell surface translocation of ROMK (Kir 1.1) channels in rat kidney cells.Mol Med Rep. 2018 Jan;17(1):1031-1034. doi: 10.3892/mmr.2017.7969. Epub 2017 Nov 6.
• [3] Renoprotective effect of tectorigenin glycosides isolated from Iris spuria L. (Zeal) against hyperoxaluria and hyperglycemia in NRK-49Fcells.Nat Prod Res. 2021 Mar;35(6):1029-1034. doi: 10.1080/14786419.2019.1613396. Epub 2019 May 28.
• [4] Expression of TGF-beta gene in adult T cell leukemia.Blood. 1988 Jan;71(1):263-6.
• [5] The role of nuclear factor erythroid-2-related factor 2 expression in radiocontrast-induced nephropathy.Sci Rep. 2019 Feb 22;9(1):2608. doi: 10.1038/s41598-019-39534-2.
• [6] Total Extracts of Abelmoschus manihot L. Attenuates Adriamycin-Induced Renal Tubule Injury via Suppression of ROS-ERK1/2-Mediated NLRP3 Inflammasome Activation.Front Pharmacol. 2019 May 28;10:567. doi: 10.3389/fphar.2019.00567. eCollection 2019.
• [7] Anti-inflammatory and renal protective effect of gingerol in high-fat diet/streptozotocin-induced diabetic rats via inflammatory mechanism.Inflammopharmacology. 2019 Dec;27(6):1243-1254. doi: 10.1007/s10787-019-00569-6. Epub 2019 Mar 2.
• [8] Ski-related novel protein suppresses the development of diabetic nephropathy by modulating transforming growth factor- signaling and microRNA-21 expression.J Cell Physiol. 2019 Aug;234(10):17925-17936. doi: 10.1002/jcp.28425. Epub 2019 Mar 7.
• [9] Major Differences in Hypoxia Tolerance and P38 Regulation Among Different Renal Cells.Cell Physiol Biochem. 2018;46(4):1483-1492. doi: 10.1159/000489188. Epub 2018 Apr 19.
• [10] Oleanolic acid attenuated diabetic mesangial cell injury by activation of autophagy via miRNA-142-5p/PTEN signaling.Cytotechnology. 2019 Oct;71(5):925-933. doi: 10.1007/s10616-019-00335-0. Epub 2019 Aug 13.
• [11] Protective effect of berberine on high glucose and hypoxia-induced apoptosis via the modulation of HIF-1 in renal tubular epithelial cells.Am J Transl Res. 2019 Feb 15;11(2):669-682. eCollection 2019.
• [12] Puerarin improves methotrexate-induced renal damage by up-regulating renal expression of Oat1 and Oat3 in vivo and in vitro.Biomed Pharmacother. 2018 Jul;103:915-922. doi: 10.1016/j.biopha.2018.04.122. Epub 2018 Apr 24.
• [13] Marfanoid hypermobility caused by an 862 kb deletion of Xq22.3 in a patient with Sotos syndrome.Am J Med Genet A. 2011 Sep;155A(9):2293-7. doi: 10.1002/ajmg.a.34164. Epub 2011 Aug 10.
• [14] 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.
• [15] 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.
• [16] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [17] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [18] 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.
• [19] 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.
• [20] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [21] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [22] 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.