Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8PQSO1)

• DOT Name: Serine/threonine-protein kinase Nek6 (NEK6)
• Synonyms: EC 2.7.11.34; Never in mitosis A-related kinase 6; NimA-related protein kinase 6; Protein kinase SID6-1512
• Gene Name: NEK6
• UniProt ID: NEK6_HUMAN
• EC Number: 2.7.11.34
• Pfam ID: PF00069
• Sequence:
  MAGQPGHMPHGGSSNNLCHTLGPVHPPDPQRHPNTLSFRCSLADFQIEKKIGRGQFSEVY
  KATCLLDRKTVALKKVQIFEMMDAKARQDCVKEIGLLKQLNHPNIIKYLDSFIEDNELNI
  VLELADAGDLSQMIKYFKKQKRLIPERTVWKYFVQLCSAVEHMHSRRVMHRDIKPANVFI
  TATGVVKLGDLGLGRFFSSETTAAHSLVGTPYYMSPERIHENGYNFKSDIWSLGCLLYEM
  AALQSPFYGDKMNLFSLCQKIEQCDYPPLPGEHYSEKLRELVSMCICPDPHQRPDIGYVH
  QVAKQMHIWMSST
• Function: Protein kinase which plays an important role in mitotic cell cycle progression. Required for chromosome segregation at metaphase-anaphase transition, robust mitotic spindle formation and cytokinesis. Phosphorylates ATF4, CIR1, PTN, RAD26L, RBBP6, RPS7, RPS6KB1, TRIP4, STAT3 and histones H1 and H3. Phosphorylates KIF11 to promote mitotic spindle formation. Involved in G2/M phase cell cycle arrest induced by DNA damage. Inhibition of activity results in apoptosis. May contribute to tumorigenesis by suppressing p53/TP53-induced cancer cell senescence. Phosphorylates EML4 at 'Ser-144', promoting its dissociation from microtubules during mitosis which is required for efficient chromosome congression.
• Tissue Specificity: Ubiquitous, with highest expression in heart and skeletal muscle.
• Reactome Pathway:
  Nuclear Pore Complex (NPC) Disassembly (R-HSA-3301854)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)
  Activation of NIMA Kinases NEK9, NEK6, NEK7 (R-HSA-2980767)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Serine/threonine-protein kinase Nek6 (NEK6).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Serine/threonine-protein kinase Nek6 (NEK6).	[8]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Serine/threonine-protein kinase Nek6 (NEK6).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Serine/threonine-protein kinase Nek6 (NEK6).	[12]

8 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 Serine/threonine-protein kinase Nek6 (NEK6).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Serine/threonine-protein kinase Nek6 (NEK6).	[3]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Serine/threonine-protein kinase Nek6 (NEK6).	[4]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Serine/threonine-protein kinase Nek6 (NEK6).	[5]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Serine/threonine-protein kinase Nek6 (NEK6).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Serine/threonine-protein kinase Nek6 (NEK6).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Serine/threonine-protein kinase Nek6 (NEK6).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Serine/threonine-protein kinase Nek6 (NEK6).	[10]

References

• [1] 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.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [6] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] 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.
• [9] Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma. Int J Cancer. 2015 May 1;136(9):2055-64.
• [10] 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.
• [11] 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.
• [12] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.