Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTI7MCML)

• DOT Name: Mitogen-activated protein kinase kinase kinase 2 (MAP3K2)
• Synonyms: EC 2.7.11.25; MAPK/ERK kinase kinase 2; MEK kinase 2; MEKK 2
• Gene Name: MAP3K2
• UniProt ID: M3K2_HUMAN
• PDB ID: 2CU1; 2NPT; 5EX0; 5HQ8; 6LDV; 6LDW; 6LDX; 6LDY
• EC Number: 2.7.11.25
• Pfam ID: PF00564 ; PF00069
• Sequence:
  MDDQQALNSIMQDLAVLHKASRPALSLQETRKAKSSSPKKQNDVRVKFEHRGEKRILQFP
  RPVKLEDLRSKAKIAFGQSMDLHYTNNELVIPLTTQDDLDKAVELLDRSIHMKSLKILLV
  INGSTQATNLEPLPSLEDLDNTVFGAERKKRLSIIGPTSRDRSSPPPGYIPDELHQVARN
  GSFTSINSEGEFIPESMDQMLDPLSLSSPENSGSGSCPSLDSPLDGESYPKSRMPRAQSY
  PDNHQEFSDYDNPIFEKFGKGGTYPRRYHVSYHHQEYNDGRKTFPRARRTQGTSLRSPVS
  FSPTDHSLSTSSGSSIFTPEYDDSRIRRRGSDIDNPTLTVMDISPPSRSPRAPTNWRLGK
  LLGQGAFGRVYLCYDVDTGRELAVKQVQFDPDSPETSKEVNALECEIQLLKNLLHERIVQ
  YYGCLRDPQEKTLSIFMEYMPGGSIKDQLKAYGALTENVTRKYTRQILEGVHYLHSNMIV
  HRDIKGANILRDSTGNVKLGDFGASKRLQTICLSGTGMKSVTGTPYWMSPEVISGEGYGR
  KADIWSVACTVVEMLTEKPPWAEFEAMAAIFKIATQPTNPKLPPHVSDYTRDFLKRIFVE
  AKLRPSADELLRHMFVHYH
• Function: Component of a protein kinase signal transduction cascade. Regulates the JNK and ERK5 pathways by phosphorylating and activating MAP2K5 and MAP2K7. Plays a role in caveolae kiss-and-run dynamics.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Gap junction (hsa04540)
  GnRH sig.ling pathway (hsa04912)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Mitogen-activated protein kinase kinase kinase 2 (MAP3K2).	[1]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Mitogen-activated protein kinase kinase kinase 2 (MAP3K2).	[2]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Mitogen-activated protein kinase kinase kinase 2 (MAP3K2).	[4]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Mitogen-activated protein kinase kinase kinase 2 (MAP3K2).	[5]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Mitogen-activated protein kinase kinase kinase 2 (MAP3K2).	[6]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Mitogen-activated protein kinase kinase kinase 2 (MAP3K2).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Mitogen-activated protein kinase kinase kinase 2 (MAP3K2).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Mitogen-activated protein kinase kinase kinase 2 (MAP3K2).	[9]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Mitogen-activated protein kinase kinase kinase 2 (MAP3K2).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Mitogen-activated protein kinase kinase kinase 2 (MAP3K2).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Mitogen-activated protein kinase kinase kinase 2 (MAP3K2).	[3]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Mitogen-activated protein kinase kinase kinase 2 (MAP3K2).	[3]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Mitogen-activated protein kinase kinase kinase 2 (MAP3K2).	[3]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [3] 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.
• [4] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [5] 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.
• [6] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [7] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [8] 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.
• [9] 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.
• [10] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [11] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.