Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT53LJGW)

• DOT Name: Mitogen-activated protein kinase kinase kinase 3 (MAP3K3)
• Synonyms: EC 2.7.11.25; MAPK/ERK kinase kinase 3; MEK kinase 3; MEKK 3
• Gene Name: MAP3K3
• UniProt ID: M3K3_HUMAN
• PDB ID: 2C60; 2JRH; 2O2V; 2PPH; 4Y5O; 4YL6
• EC Number: 2.7.11.25
• Pfam ID: PF00564 ; PF00069
• Sequence:
  MDEQEALNSIMNDLVALQMNRRHRMPGYETMKNKDTGHSNRQSDVRIKFEHNGERRIIAF
  SRPVKYEDVEHKVTTVFGQPLDLHYMNNELSILLKNQDDLDKAIDILDRSSSMKSLRILL
  LSQDRNHNSSSPHSGVSRQVRIKASQSAGDINTIYQPPEPRSRHLSVSSQNPGRSSPPPG
  YVPERQQHIARQGSYTSINSEGEFIPETSEQCMLDPLSSAENSLSGSCQSLDRSADSPSF
  RKSRMSRAQSFPDNRQEYSDRETQLYDKGVKGGTYPRRYHVSVHHKDYSDGRRTFPRIRR
  HQGNLFTLVPSSRSLSTNGENMGLAVQYLDPRGRLRSADSENALSVQERNVPTKSPSAPI
  NWRRGKLLGQGAFGRVYLCYDVDTGRELASKQVQFDPDSPETSKEVSALECEIQLLKNLQ
  HERIVQYYGCLRDRAEKTLTIFMEYMPGGSVKDQLKAYGALTESVTRKYTRQILEGMSYL
  HSNMIVHRDIKGANILRDSAGNVKLGDFGASKRLQTICMSGTGMRSVTGTPYWMSPEVIS
  GEGYGRKADVWSLGCTVVEMLTEKPPWAEYEAMAAIFKIATQPTNPQLPSHISEHGRDFL
  RRIFVEARQRPSAEELLTHHFAQLMY
• Function: Component of a protein kinase signal transduction cascade. Mediates activation of the NF-kappa-B, AP1 and DDIT3 transcriptional regulators.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Neurotrophin sig.ling pathway (hsa04722)
  GnRH sig.ling pathway (hsa04912)
  Human T-cell leukemia virus 1 infection (hsa05166)
  PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235)
• Reactome Pathway: Interleukin-1 signaling (R-HSA-9020702)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Mitogen-activated protein kinase kinase kinase 3 (MAP3K3).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Mitogen-activated protein kinase kinase kinase 3 (MAP3K3).	[2]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Mitogen-activated protein kinase kinase kinase 3 (MAP3K3).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Mitogen-activated protein kinase kinase kinase 3 (MAP3K3).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Mitogen-activated protein kinase kinase kinase 3 (MAP3K3).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Mitogen-activated protein kinase kinase kinase 3 (MAP3K3).	[6]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Mitogen-activated protein kinase kinase kinase 3 (MAP3K3).	[7]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Mitogen-activated protein kinase kinase kinase 3 (MAP3K3).	[8]
Romidepsin	DMT5GNL	Approved	Romidepsin increases the expression of Mitogen-activated protein kinase kinase kinase 3 (MAP3K3).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Mitogen-activated protein kinase kinase kinase 3 (MAP3K3).	[10]
Rigosertib	DMOSTXF	Phase 3	Rigosertib affects the expression of Mitogen-activated protein kinase kinase kinase 3 (MAP3K3).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Mitogen-activated protein kinase kinase kinase 3 (MAP3K3).	[13]
Deguelin	DMXT7WG	Investigative	Deguelin affects the expression of Mitogen-activated protein kinase kinase kinase 3 (MAP3K3).	[14]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Mitogen-activated protein kinase kinase kinase 3 (MAP3K3).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Mitogen-activated protein kinase kinase kinase 3 (MAP3K3).	[12]

References

• [1] 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.
• [2] 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.
• [3] 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.
• [4] Prenatal arsenic exposure and the epigenome: altered microRNAs associated with innate and adaptive immune signaling in newborn cord blood. Environ Mol Mutagen. 2014 Apr;55(3):196-208. doi: 10.1002/em.21842. Epub 2013 Dec 10.
• [5] Quercetin inhibits migration and invasion of SAS human oral cancer cells through inhibition of NF-B and matrix metalloproteinase-2/-9 signaling pathways. Anticancer Res. 2013 May;33(5):1941-50.
• [6] 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.
• [7] Transcriptomic Analysis of Stem Cells Treated with Moringin or Cannabidiol: Analogies and Differences in Inflammation Pathways. Int J Mol Sci. 2019 Nov 30;20(23):6039. doi: 10.3390/ijms20236039.
• [8] 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.
• [9] 5-Aza-2'-deoxycytidine and depsipeptide synergistically induce expression of BIK (BCL2-interacting killer). Biochem Biophys Res Commun. 2006 Dec 15;351(2):455-61. doi: 10.1016/j.bbrc.2006.10.055. Epub 2006 Oct 18.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] ON 01910.Na is selectively cytotoxic for chronic lymphocytic leukemia cells through a dual mechanism of action involving PI3K/AKT inhibition and induction of oxidative stress. Clin Cancer Res. 2012 Apr 1;18(7):1979-91. doi: 10.1158/1078-0432.CCR-11-2113. Epub 2012 Feb 20.
• [12] 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.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [14] Deguelin inhibits the migration and invasion of U-2 OS human osteosarcoma cells via the inhibition of matrix metalloproteinase-2/-9 in vitro. Molecules. 2014 Oct 15;19(10):16588-608.
• [15] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.