Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS3FVTY)

• DOT Name: Mitogen-activated protein kinase kinase kinase 1 (MAP3K1)
• Synonyms: EC 2.7.11.25; MAPK/ERK kinase kinase 1; MEK kinase 1; MEKK 1; EC 2.3.2.27
• Gene Name: MAP3K1
• Related Disease:
  46,XY sex reversal 6
  46,XY complete gonadal dysgenesis
  46,XY partial gonadal dysgenesis
• UniProt ID: M3K1_HUMAN
• PDB ID: 6WHB
• EC Number: 2.3.2.27; 2.7.11.25
• Pfam ID: PF21040 ; PF00069 ; PF04434
• Sequence:
  MAAAAGNRASSSGFPGARATSPEAGGGGGALKASSAPAAAAGLLREAGSGGRERADWRRR
  QLRKVRSVELDQLPEQPLFLAASPPASSTSPSPEPADAAGSGTGFQPVAVPPPHGAASRG
  GAHLTESVAAPDSGASSPAAAEPGEKRAPAAEPSPAAAPAGREMENKETLKGLHKMDDRP
  EERMIREKLKATCMPAWKHEWLERRNRRGPVVVKPIPVKGDGSEMNHLAAESPGEVQASA
  ASPASKGRRSPSPGNSPSGRTVKSESPGVRRKRVSPVPFQSGRITPPRRAPSPDGFSPYS
  PEETNRRVNKVMRARLYLLQQIGPNSFLIGGDSPDNKYRVFIGPQNCSCARGTFCIHLLF
  VMLRVFQLEPSDPMLWRKTLKNFEVESLFQKYHSRRSSRIKAPSRNTIQKFVSRMSNSHT
  LSSSSTSTSSSENSIKDEEEQMCPICLLGMLDEESLTVCEDGCRNKLHHHCMSIWAEECR
  RNREPLICPLCRSKWRSHDFYSHELSSPVDSPSSLRAAQQQTVQQQPLAGSRRNQESNFN
  LTHYGTQQIPPAYKDLAEPWIQVFGMELVGCLFSRNWNVREMALRRLSHDVSGALLLANG
  ESTGNSGGSSGSSPSGGATSGSSQTSISGDVVEACCSVLSMVCADPVYKVYVAALKTLRA
  MLVYTPCHSLAERIKLQRLLQPVVDTILVKCADANSRTSQLSISTLLELCKGQAGELAVG
  REILKAGSIGIGGVDYVLNCILGNQTESNNWQELLGRLCLIDRLLLEFPAEFYPHIVSTD
  VSQAEPVEIRYKKLLSLLTFALQSIDNSHSMVGKLSRRIYLSSARMVTTVPHVFSKLLEM
  LSVSSSTHFTRMRRRLMAIADEVEIAEAIQLGVEDTLDGQQDSFLQASVPNNYLETTENS
  SPECTVHLEKTGKGLCATKLSASSEDISERLASISVGPSSSTTTTTTTTEQPKPMVQTKG
  RPHSQCLNSSPLSHHSQLMFPALSTPSSSTPSVPAGTATDVSKHRLQGFIPCRIPSASPQ
  TQRKFSLQFHRNCPENKDSDKLSPVFTQSRPLPSSNIHRPKPSRPTPGNTSKQGDPSKNS
  MTLDLNSSSKCDDSFGCSSNSSNAVIPSDETVFTPVEEKCRLDVNTELNSSIEDLLEASM
  PSSDTTVTFKSEVAVLSPEKAENDDTYKDDVNHNQKCKEKMEAEEEEALAIAMAMSASQD
  ALPIVPQLQVENGEDIIIIQQDTPETLPGHTKAKQPYREDTEWLKGQQIGLGAFSSCYQA
  QDVGTGTLMAVKQVTYVRNTSSEQEEVVEALREEIRMMSHLNHPNIIRMLGATCEKSNYN
  LFIEWMAGGSVAHLLSKYGAFKESVVINYTEQLLRGLSYLHENQIIHRDVKGANLLIDST
  GQRLRIADFGAAARLASKGTGAGEFQGQLLGTIAFMAPEVLRGQQYGRSCDVWSVGCAII
  EMACAKPPWNAEKHSNHLALIFKIASATTAPSIPSHLSPGLRDVALRCLELQPQDRPPSR
  ELLKHPVFRTTW
• Function: Component of a protein kinase signal transduction cascade. Activates the ERK and JNK kinase pathways by phosphorylation of MAP2K1 and MAP2K4. May phosphorylate the MAPK8/JNK1 kinase. Activates CHUK and IKBKB, the central protein kinases of the NF-kappa-B pathway.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Ubiquitin mediated proteolysis (hsa04120)
  Tight junction (hsa04530)
  RIG-I-like receptor sig.ling pathway (hsa04622)
  Neurotrophin sig.ling pathway (hsa04722)
  GnRH sig.ling pathway (hsa04912)
  Growth hormone synthesis, secretion and action (hsa04935)
  Hepatitis B (hsa05161)
  Human T-cell leukemia virus 1 infection (hsa05166)
• Reactome Pathway:
  FCERI mediated MAPK activation (R-HSA-2871796)
  TRAF6 mediated NF-kB activation (R-HSA-933542)
  TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation (R-HSA-975138)
  MyD88 cascade initiated on plasma membrane (R-HSA-975871)
  MyD88 (R-HSA-166058)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
46,XY sex reversal 6	DISSHCUW	Definitive	Autosomal dominant	[1]
46,XY complete gonadal dysgenesis	DISLF3LT	Supportive	Autosomal dominant	[1]
46,XY partial gonadal dysgenesis	DISMNH0C	Supportive	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Dacarbazine	DMNPZL4	Approved	Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) decreases the response to substance of Dacarbazine.	[25]

4 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 Mitogen-activated protein kinase kinase kinase 1 (MAP3K1).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the methylation of Mitogen-activated protein kinase kinase kinase 1 (MAP3K1).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Mitogen-activated protein kinase kinase kinase 1 (MAP3K1).	[17]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Mitogen-activated protein kinase kinase kinase 1 (MAP3K1).	[19]

19 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 Mitogen-activated protein kinase kinase kinase 1 (MAP3K1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mitogen-activated protein kinase kinase kinase 1 (MAP3K1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mitogen-activated protein kinase kinase kinase 1 (MAP3K1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Mitogen-activated protein kinase kinase kinase 1 (MAP3K1).	[6]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Mitogen-activated protein kinase kinase kinase 1 (MAP3K1).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Mitogen-activated protein kinase kinase kinase 1 (MAP3K1).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Mitogen-activated protein kinase kinase kinase 1 (MAP3K1).	[10]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Mitogen-activated protein kinase kinase kinase 1 (MAP3K1).	[11]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Mitogen-activated protein kinase kinase kinase 1 (MAP3K1).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Mitogen-activated protein kinase kinase kinase 1 (MAP3K1).	[14]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Mitogen-activated protein kinase kinase kinase 1 (MAP3K1).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Mitogen-activated protein kinase kinase kinase 1 (MAP3K1).	[18]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Mitogen-activated protein kinase kinase kinase 1 (MAP3K1).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Mitogen-activated protein kinase kinase kinase 1 (MAP3K1).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Mitogen-activated protein kinase kinase kinase 1 (MAP3K1).	[22]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Mitogen-activated protein kinase kinase kinase 1 (MAP3K1).	[23]
ELLAGIC ACID	DMX8BS5	Investigative	ELLAGIC ACID decreases the expression of Mitogen-activated protein kinase kinase kinase 1 (MAP3K1).	[24]
I-BET151	DMYRUH2	Investigative	I-BET151 decreases the expression of Mitogen-activated protein kinase kinase kinase 1 (MAP3K1).	[18]
PFI-1	DMVFK3J	Investigative	PFI-1 decreases the expression of Mitogen-activated protein kinase kinase kinase 1 (MAP3K1).	[18]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the cleavage of Mitogen-activated protein kinase kinase kinase 1 (MAP3K1).	[12]
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Mitogen-activated protein kinase kinase kinase 1 (MAP3K1).	[16]

References

• [1] Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction pathway in human testis determination. Am J Hum Genet. 2010 Dec 10;87(6):898-904. doi: 10.1016/j.ajhg.2010.11.003.
• [2] 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.
• [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] 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.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Arsenic and the epigenome: interindividual differences in arsenic metabolism related to distinct patterns of DNA methylation. J Biochem Mol Toxicol. 2013 Feb;27(2):106-15. doi: 10.1002/jbt.21462. Epub 2013 Jan 11.
• [8] Quercetin potentiates apoptosis by inhibiting nuclear factor-kappaB signaling in H460 lung cancer cells. Biol Pharm Bull. 2013;36(6):944-51. doi: 10.1248/bpb.b12-01004.
• [9] 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.
• [10] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [11] New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids. Arch Toxicol. 2021 Aug;95(8):2691-2718. doi: 10.1007/s00204-021-03092-2. Epub 2021 Jun 20.
• [12] Involvement of Asp-Glu-Val-Asp-directed, caspase-mediated mitogen-activated protein kinase kinase 1 Cleavage, c-Jun N-terminal kinase activation, and subsequent Bcl-2 phosphorylation for paclitaxel-induced apoptosis in HL-60 cells. Mol Pharmacol. 2001 Feb;59(2):254-62. doi: 10.1124/mol.59.2.254.
• [13] 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.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Gene expression profiling identifies activating transcription factor 3 as a novel contributor to the proapoptotic effect of curcumin. Mol Cancer Ther. 2005 Feb;4(2):233-41.
• [16] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [17] 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.
• [18] BRD4 is a novel therapeutic target for liver fibrosis. Proc Natl Acad Sci U S A. 2015 Dec 22;112(51):15713-8. doi: 10.1073/pnas.1522163112. Epub 2015 Dec 7.
• [19] 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.
• [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] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [23] 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.
• [24] In vitro antioxidant and antiproliferative effects of ellagic acid and its colonic metabolite, urolithins, on human bladder cancer T24 cells. Food Chem Toxicol. 2013 Sep;59:428-37. doi: 10.1016/j.fct.2013.06.025. Epub 2013 Jun 26.
• [25] Exposure of melanoma cells to dacarbazine results in enhanced tumor growth and metastasis in vivo. J Clin Oncol. 2004 Jun 1;22(11):2092-100. doi: 10.1200/JCO.2004.11.070. Epub 2004 May 3.