Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT3DOOL)

• DOT Name: Mitogen-activated protein kinase kinase kinase 14 (MAP3K14)
• Synonyms: EC 2.7.11.25; NF-kappa-beta-inducing kinase; HsNIK; Serine/threonine-protein kinase NIK
• Gene Name: MAP3K14
• Related Disease: NIK deficiency
• UniProt ID: M3K14_HUMAN
• PDB ID: 4DN5; 4G3D; 4IDT; 4IDV; 6WPP; 6Z1Q; 6Z1T
• EC Number: 2.7.11.25
• Pfam ID: PF00069
• Sequence:
  MAVMEMACPGAPGSAVGQQKELPKAKEKTPPLGKKQSSVYKLEAVEKSPVFCGKWEILND
  VITKGTAKEGSEAGPAAISIIAQAECENSQEFSPTFSERIFIAGSKQYSQSESLDQIPNN
  VAHATEGKMARVCWKGKRRSKARKKRKKKSSKSLAHAGVALAKPLPRTPEQESCTIPVQE
  DESPLGAPYVRNTPQFTKPLKEPGLGQLCFKQLGEGLRPALPRSELHKLISPLQCLNHVW
  KLHHPQDGGPLPLPTHPFPYSRLPHPFPFHPLQPWKPHPLESFLGKLACVDSQKPLPDPH
  LSKLACVDSPKPLPGPHLEPSCLSRGAHEKFSVEEYLVHALQGSVSSGQAHSLTSLAKTW
  AARGSRSREPSPKTEDNEGVLLTEKLKPVDYEYREEVHWATHQLRLGRGSFGEVHRMEDK
  QTGFQCAVKKVRLEVFRAEELMACAGLTSPRIVPLYGAVREGPWVNIFMELLEGGSLGQL
  VKEQGCLPEDRALYYLGQALEGLEYLHSRRILHGDVKADNVLLSSDGSHAALCDFGHAVC
  LQPDGLGKSLLTGDYIPGTETHMAPEVVLGRSCDAKVDVWSSCCMMLHMLNGCHPWTQFF
  RGPLCLKIASEPPPVREIPPSCAPLTAQAIQEGLRKEPIHRVSAAELGGKVNRALQQVGG
  LKSPWRGEYKEPRHPPPNQANYHQTLHAQPRELSPRAPGPRPAEETTGRAPKLQPPLPPE
  PPEPNKSPPLTLSKEESGMWEPLPLSSLEPAPARNPSSPERKATVPEQELQQLEIELFLN
  SLSQPFSLEEQEQILSCLSIDSLSLSDDSEKNPSKASQSSRDTLSSGVHSWSSQAEARSS
  SWNMVLARGRPTDTPSYFNGVKVQIQSLNGEHLHIREFHRVKVGDIATGISSQIPAAAFS
  LVTKDGQPVRYDMEVPDSGIDLQCTLAPDGSFAWSWRVKHGQLENRP
• Function: Lymphotoxin beta-activated kinase which seems to be exclusively involved in the activation of NF-kappa-B and its transcriptional activity. Phosphorylates CHUK/IKKA, thereby promoting proteolytic processing of NFKB2/P100, which leads to NF-kappa-B activation via the non-canonical pathway. Has an essential role in the non-canonical NF-kappa-B signaling that regulates genes encoding molecules involved in B-cell survival, lymphoid organogenesis, and immune response. Could act in a receptor-selective manner.
• Tissue Specificity: Weakly expressed in testis, small intestine, spleen, thymus, peripheral blood leukocytes, prostate, ovary and colon.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  NF-kappa B sig.ling pathway (hsa04064)
  Apoptosis (hsa04210)
  Osteoclast differentiation (hsa04380)
  C-type lectin receptor sig.ling pathway (hsa04625)
  T cell receptor sig.ling pathway (hsa04660)
  TNF sig.ling pathway (hsa04668)
  Intesti.l immune network for IgA production (hsa04672)
  Alcoholic liver disease (hsa04936)
  Epithelial cell sig.ling in Helicobacter pylori infection (hsa05120)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Epstein-Barr virus infection (hsa05169)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
• Reactome Pathway:
  Dectin-1 mediated noncanonical NF-kB signaling (R-HSA-5607761)
  TNFR2 non-canonical NF-kB pathway (R-HSA-5668541)
  NIK-->noncanonical NF-kB signaling (R-HSA-5676590)
  TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway (R-HSA-5676594)
  CD28 dependent PI3K/Akt signaling (R-HSA-389357)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
NIK deficiency	DISQPISX	Moderate	Autosomal recessive	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Ibrutinib	DMHZCPO	Approved	Mitogen-activated protein kinase kinase kinase 14 (MAP3K14) decreases the response to substance of Ibrutinib.	[24]

21 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 Mitogen-activated protein kinase kinase kinase 14 (MAP3K14).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Mitogen-activated protein kinase kinase kinase 14 (MAP3K14).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Mitogen-activated protein kinase kinase kinase 14 (MAP3K14).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Mitogen-activated protein kinase kinase kinase 14 (MAP3K14).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Mitogen-activated protein kinase kinase kinase 14 (MAP3K14).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Mitogen-activated protein kinase kinase kinase 14 (MAP3K14).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Mitogen-activated protein kinase kinase kinase 14 (MAP3K14).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Mitogen-activated protein kinase kinase kinase 14 (MAP3K14).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Mitogen-activated protein kinase kinase kinase 14 (MAP3K14).	[10]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Mitogen-activated protein kinase kinase kinase 14 (MAP3K14).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Mitogen-activated protein kinase kinase kinase 14 (MAP3K14).	[11]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Mitogen-activated protein kinase kinase kinase 14 (MAP3K14).	[12]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the expression of Mitogen-activated protein kinase kinase kinase 14 (MAP3K14).	[13]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Mitogen-activated protein kinase kinase kinase 14 (MAP3K14).	[14]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Mitogen-activated protein kinase kinase kinase 14 (MAP3K14).	[15]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Mitogen-activated protein kinase kinase kinase 14 (MAP3K14).	[16]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Mitogen-activated protein kinase kinase kinase 14 (MAP3K14).	[17]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Mitogen-activated protein kinase kinase kinase 14 (MAP3K14).	[18]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Mitogen-activated protein kinase kinase kinase 14 (MAP3K14).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Mitogen-activated protein kinase kinase kinase 14 (MAP3K14).	[21]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Mitogen-activated protein kinase kinase kinase 14 (MAP3K14).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Mitogen-activated protein kinase kinase kinase 14 (MAP3K14).	[20]
MANGIFERIN	DMWAF5Z	Investigative	MANGIFERIN decreases the phosphorylation of Mitogen-activated protein kinase kinase kinase 14 (MAP3K14).	[23]

References

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• [2] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [3] 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.
• [4] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [9] 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.
• [10] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [11] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [12] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [13] Simvastatin potentiates TNF-alpha-induced apoptosis through the down-regulation of NF-kappaB-dependent antiapoptotic gene products: role of IkappaBalpha kinase and TGF-beta-activated kinase-1. J Immunol. 2007 Feb 15;178(4):2507-16. doi: 10.4049/jimmunol.178.4.2507.
• [14] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] A novel long noncoding RNA AK001796 acts as an oncogene and is involved in cell growth inhibition by resveratrol in lung cancer. Toxicol Appl Pharmacol. 2015 Jun 1;285(2):79-88.
• [17] New TNF-alpha releasing inhibitors as cancer preventive agents from traditional herbal medicine and combination cancer prevention study with EGCG and sulindac or tamoxifen. Mutat Res. 2003 Feb-Mar;523-524:119-25. doi: 10.1016/s0027-5107(02)00327-5.
• [18] A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
• [19] Arsenic mediates cell proliferation and gene expression in the bladder epithelium: association with activating protein-1 transactivation. Cancer Res. 2000 Jul 1;60(13):3445-53.
• [20] 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.
• [21] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [22] Probiotic Bacillus subtilis CW14 reduces disruption of the epithelial barrier and toxicity of ochratoxin A to Caco-2?cells. Food Chem Toxicol. 2019 Apr;126:25-33. doi: 10.1016/j.fct.2019.02.009. Epub 2019 Feb 11.
• [23] Mangiferin induces apoptosis in multiple myeloma cell lines by suppressing the activation of nuclear factor kappa B-inducing kinase. Chem Biol Interact. 2016 May 5;251:26-33. doi: 10.1016/j.cbi.2016.03.018. Epub 2016 Mar 17.
• [24] Synergistic activity of BET protein antagonist-based combinations in mantle cell lymphoma cells sensitive or resistant to ibrutinib. Blood. 2015 Sep 24;126(13):1565-74.