Details of Drug Off-Target (DOT)

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

• DOT Name: MAP kinase-interacting serine/threonine-protein kinase 1 (MKNK1)
• Synonyms: EC 2.7.11.1; MAP kinase signal-integrating kinase 1; MAPK signal-integrating kinase 1; Mnk1
• Gene Name: MKNK1
• UniProt ID: MKNK1_HUMAN
• PDB ID: 2HW6; 2Y9Q; 5WVD
• EC Number: 2.7.11.1
• Pfam ID: PF00069
• Sequence:
  MVSSQKLEKPIEMGSSEPLPIADGDRRRKKKRRGRATDSLPGKFEDMYKLTSELLGEGAY
  AKVQGAVSLQNGKEYAVKIIEKQAGHSRSRVFREVETLYQCQGNKNILELIEFFEDDTRF
  YLVFEKLQGGSILAHIQKQKHFNEREASRVVRDVAAALDFLHTKDKVSLCHLGWSAMAPS
  GLTAAPTSLGSSDPPTSASQVAGTTGIAHRDLKPENILCESPEKVSPVKICDFDLGSGMK
  LNNSCTPITTPELTTPCGSAEYMAPEVVEVFTDQATFYDKRCDLWSLGVVLYIMLSGYPP
  FVGHCGADCGWDRGEVCRVCQNKLFESIQEGKYEFPDKDWAHISSEAKDLISKLLVRDAK
  QRLSAAQVLQHPWVQGQAPEKGLPTPQVLQRNSSTMDLTLFAAEAIALNRQLSQHEENEL
  AEEPEALADGLCSMKLSPPCKSRLARRRALAQAGRGEDRSPPTAL
• Function: May play a role in the response to environmental stress and cytokines. Appears to regulate translation by phosphorylating EIF4E, thus increasing the affinity of this protein for the 7-methylguanosine-containing mRNA cap.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  HIF-1 sig.ling pathway (hsa04066)
  Insulin sig.ling pathway (hsa04910)
• Reactome Pathway: Spry regulation of FGF signaling (R-HSA-1295596)

Molecular Interaction Atlas (MIA) of This DOT

2 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 MAP kinase-interacting serine/threonine-protein kinase 1 (MKNK1).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of MAP kinase-interacting serine/threonine-protein kinase 1 (MKNK1).	[12]

15 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 MAP kinase-interacting serine/threonine-protein kinase 1 (MKNK1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of MAP kinase-interacting serine/threonine-protein kinase 1 (MKNK1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of MAP kinase-interacting serine/threonine-protein kinase 1 (MKNK1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of MAP kinase-interacting serine/threonine-protein kinase 1 (MKNK1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of MAP kinase-interacting serine/threonine-protein kinase 1 (MKNK1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of MAP kinase-interacting serine/threonine-protein kinase 1 (MKNK1).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of MAP kinase-interacting serine/threonine-protein kinase 1 (MKNK1).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the activity of MAP kinase-interacting serine/threonine-protein kinase 1 (MKNK1).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of MAP kinase-interacting serine/threonine-protein kinase 1 (MKNK1).	[10]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of MAP kinase-interacting serine/threonine-protein kinase 1 (MKNK1).	[6]
Phosphate	DMUXQG7	Approved	Phosphate increases the expression of MAP kinase-interacting serine/threonine-protein kinase 1 (MKNK1).	[11]
Sorbitol	DMAN0DE	Approved	Sorbitol increases the activity of MAP kinase-interacting serine/threonine-protein kinase 1 (MKNK1).	[9]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the activity of MAP kinase-interacting serine/threonine-protein kinase 1 (MKNK1).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of MAP kinase-interacting serine/threonine-protein kinase 1 (MKNK1).	[13]
CGP-57380	DMFPOUC	Investigative	CGP-57380 decreases the activity of MAP kinase-interacting serine/threonine-protein kinase 1 (MKNK1).	[14]

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] 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.
• [3] 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.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] Estrogen Regulates MAPK-Related Genes through Genomic and Nongenomic Interactions between IGF-I Receptor Tyrosine Kinase and Estrogen Receptor-Alpha Signaling Pathways in Human Uterine Leiomyoma Cells. J Signal Transduct. 2012;2012:204236. doi: 10.1155/2012/204236. Epub 2012 Oct 9.
• [8] Aberrantly expressed genes in HaCaT keratinocytes chronically exposed to arsenic trioxide. Biomark Insights. 2011 Feb 8;6:7-16.
• [9] The phosphorylation of eukaryotic initiation factor eIF4E in response to phorbol esters, cell stresses, and cytokines is mediated by distinct MAP kinase pathways. J Biol Chem. 1998 Apr 17;273(16):9373-7. doi: 10.1074/jbc.273.16.9373.
• [10] A genomic approach to predict synergistic combinations for breast cancer treatment. Pharmacogenomics J. 2013 Feb;13(1):94-104. doi: 10.1038/tpj.2011.48. Epub 2011 Nov 15.
• [11] Elevated inorganic phosphate stimulates Akt-ERK1/2-Mnk1 signaling in human lung cells. Am J Respir Cell Mol Biol. 2006 Nov;35(5):528-39. doi: 10.1165/rcmb.2005-0477OC. Epub 2006 Jun 8.
• [12] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [13] 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.
• [14] Regulation of arsenic trioxide-induced cellular responses by Mnk1 and Mnk2. J Biol Chem. 2008 May 2;283(18):12034-42. doi: 10.1074/jbc.M708816200. Epub 2008 Feb 25.