Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOE0Z1R)

• DOT Name: Mitogen-activated protein kinase kinase kinase 6 (MAP3K6)
• Synonyms: EC 2.7.11.25; Apoptosis signal-regulating kinase 2
• Gene Name: MAP3K6
• Related Disease:
  Hereditary diffuse gastric adenocarcinoma
  Gastric cancer
• UniProt ID: M3K6_HUMAN
• EC Number: 2.7.11.25
• Pfam ID: PF19039 ; PF20309 ; PF20302 ; PF13281 ; PF00069
• Sequence:
  MAGPCPRSGAERAGSCWQDPLAVALSRGRQLAAPPGRGCARSRPLSVVYVLTREPQPGLE
  PREGTEAEPLPLRCLREACAQVPRPRPPPQLRSLPFGTLELGDTAALDAFYNADVVVLEV
  SSSLVQPSLFYHLGVRESFSMTNNVLLCSQADLPDLQALREDVFQKNSDCVGSYTLIPYV
  VTATGRVLCGDAGLLRGLADGLVQAGVGTEALLTPLVGRLARLLEATPTDSCGYFRETIR
  RDIRQARERFSGPQLRQELARLQRRLDSVELLSPDIIMNLLLSYRDVQDYSAIIELVETL
  QALPTCDVAEQHNVCFHYTFALNRRNRPGDRAKALSVLLPLVQLEGSVAPDLYCMCGRIY
  KDMFFSSGFQDAGHREQAYHWYRKAFDVEPSLHSGINAAVLLIAAGQHFEDSKELRLIGM
  KLGCLLARKGCVEKMQYYWDVGFYLGAQILANDPTQVVLAAEQLYKLNAPIWYLVSVMET
  FLLYQHFRPTPEPPGGPPRRAHFWLHFLLQSCQPFKTACAQGDQCLVLVLEMNKVLLPAK
  LEVRGTDPVSTVTLSLLEPETQDIPSSWTFPVASICGVSASKRDERCCFLYALPPAQDVQ
  LCFPSVGHCQWFCGLIQAWVTNPDSTAPAEEAEGAGEMLEFDYEYTETGERLVLGKGTYG
  VVYAGRDRHTRVRIAIKEIPERDSRFSQPLHEEIALHRRLRHKNIVRYLGSASQGGYLKI
  FMEEVPGGSLSSLLRSVWGPLKDNESTISFYTRQILQGLGYLHDNHIVHRDIKGDNVLIN
  TFSGLLKISDFGTSKRLAGITPCTETFTGTLQYMAPEIIDQGPRGYGKAADIWSLGCTVI
  EMATGRPPFHELGSPQAAMFQVGMYKVHPPMPSSLSAEAQAFLLRTFEPDPRLRASAQTL
  LGDPFLQPGKRSRSPSSPRHAPRPSDAPSASPTPSANSTTQSQTFPCPQAPSQHPPSPPK
  RCLSYGGTSQLRVPEEPAAEEPASPEESSGLSLLHQESKRRAMLAAVLEQELPALAENLH
  QEQKQEQGARLGRNHVEELLRCLGAHIHTPNRRQLAQELRALQGRLRAQGLGPALLHRPL
  FAFPDAVKQILRKRQIRPHWMFVLDSLLSRAVRAALGVLGPEVEKEAVSPRSEELSNEGD
  SQQSPGQQSPLPVEPEQGPAPLMVQLSLLRAETDRLREILAGKEREYQALVQRALQRLNE
  EARTYVLAPEPPTALSTDQGLVQWLQELNVDSGTIQMLLNHSFTLHTLLTYATRDDLIYT
  RIRGGMVCRIWRAILAQRAGSTPVTSGP
• Function: Component of a protein kinase signal transduction cascade. Activates the JNK, but not ERK or p38 kinase pathways.
• KEGG Pathway: MAPK sig.ling pathway (hsa04010)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Supportive	Autosomal dominant	[1]
Gastric cancer	DISXGOUK	Limited	Unknown	[2]

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 Mitogen-activated protein kinase kinase kinase 6 (MAP3K6).	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mitogen-activated protein kinase kinase kinase 6 (MAP3K6).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Mitogen-activated protein kinase kinase kinase 6 (MAP3K6).	[5]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Mitogen-activated protein kinase kinase kinase 6 (MAP3K6).	[6]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Mitogen-activated protein kinase kinase kinase 6 (MAP3K6).	[7]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Mitogen-activated protein kinase kinase kinase 6 (MAP3K6).	[5]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Mitogen-activated protein kinase kinase kinase 6 (MAP3K6).	[8]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Mitogen-activated protein kinase kinase kinase 6 (MAP3K6).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Mitogen-activated protein kinase kinase kinase 6 (MAP3K6).	[10]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Mitogen-activated protein kinase kinase kinase 6 (MAP3K6).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Mitogen-activated protein kinase kinase kinase 6 (MAP3K6).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Mitogen-activated protein kinase kinase kinase 6 (MAP3K6).	[13]
PMID27336223-Compound-5	DM6E50A	Patented	PMID27336223-Compound-5 decreases the expression of Mitogen-activated protein kinase kinase kinase 6 (MAP3K6).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Mitogen-activated protein kinase kinase kinase 6 (MAP3K6).	[14]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Mitogen-activated protein kinase kinase kinase 6 (MAP3K6).	[15]

References

• [1] Germline mutations in MAP3K6 are associated with familial gastric cancer. PLoS Genet. 2014 Oct 23;10(10):e1004669. doi: 10.1371/journal.pgen.1004669. eCollection 2014 Oct.
• [2] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [3] 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.
• [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] 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.
• [6] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [7] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [8] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [9] PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med. 2006 Oct 2;203(10):2351-62.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [12] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [13] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [14] 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.
• [15] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.