Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0EYZAY)

• DOT Name: Mitogen-activated protein kinase kinase kinase 11 (MAP3K11)
• Synonyms: EC 2.7.11.25; Mixed lineage kinase 3; Src-homology 3 domain-containing proline-rich kinase
• Gene Name: MAP3K11
• UniProt ID: M3K11_HUMAN
• PDB ID: 5K26; 5K28; 6AQB; 6CQ7
• EC Number: 2.7.11.25
• Pfam ID: PF07714 ; PF14604
• Sequence:
  MEPLKSLFLKSPLGSWNGSGSGGGGGGGGGRPEGSPKAAGYANPVWTALFDYEPSGQDEL
  ALRKGDRVEVLSRDAAISGDEGWWAGQVGGQVGIFPSNYVSRGGGPPPCEVASFQELRLE
  EVIGIGGFGKVYRGSWRGELVAVKAARQDPDEDISVTAESVRQEARLFAMLAHPNIIALK
  AVCLEEPNLCLVMEYAAGGPLSRALAGRRVPPHVLVNWAVQIARGMHYLHCEALVPVIHR
  DLKSNNILLLQPIESDDMEHKTLKITDFGLAREWHKTTQMSAAGTYAWMAPEVIKASTFS
  KGSDVWSFGVLLWELLTGEVPYRGIDCLAVAYGVAVNKLTLPIPSTCPEPFAQLMADCWA
  QDPHRRPDFASILQQLEALEAQVLREMPRDSFHSMQEGWKREIQGLFDELRAKEKELLSR
  EEELTRAAREQRSQAEQLRRREHLLAQWELEVFERELTLLLQQVDRERPHVRRRRGTFKR
  SKLRARDGGERISMPLDFKHRITVQASPGLDRRRNVFEVGPGDSPTFPRFRAIQLEPAEP
  GQAWGRQSPRRLEDSSNGERRACWAWGPSSPKPGEAQNGRRRSRMDEATWYLDSDDSSPL
  GSPSTPPALNGNPPRPSLEPEEPKRPVPAERGSSSGTPKLIQRALLRGTALLASLGLGRD
  LQPPGGPGRERGESPTTPPTPTPAPCPTEPPPSPLICFSLKTPDSPPTPAPLLLDLGIPV
  GQRSAKSPRREEEPRGGTVSPPPGTSRSAPGTPGTPRSPPLGLISRPRPSPLRSRIDPWS
  FVSAGPRPSPLPSPQPAPRRAPWTLFPDSDPFWDSPPANPFQGGPQDCRAQTKDMGAQAP
  WVPEAGP
• Function: Activates the JUN N-terminal pathway. Required for serum-stimulated cell proliferation and for mitogen and cytokine activation of MAPK14 (p38), MAPK3 (ERK) and MAPK8 (JNK1) through phosphorylation and activation of MAP2K4/MKK4 and MAP2K7/MKK7. Plays a role in mitogen-stimulated phosphorylation and activation of BRAF, but does not phosphorylate BRAF directly. Influences microtubule organization during the cell cycle.
• Tissue Specificity: Expressed in a wide variety of normal and neoplastic tissues including fetal lung, liver, heart and kidney, and adult lung, liver, heart, kidney, placenta, skeletal muscle, pancreas and brain.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Non-alcoholic fatty liver disease (hsa04932)
• Reactome Pathway:
  Signaling by moderate kinase activity BRAF mutants (R-HSA-6802946)
  Paradoxical activation of RAF signaling by kinase inactive BRAF (R-HSA-6802955)
  CDC42 GTPase cycle (R-HSA-9013148)
  RHOG GTPase cycle (R-HSA-9013408)
  RHOV GTPase cycle (R-HSA-9013424)
  Signaling downstream of RAS mutants (R-HSA-9649948)
  RAF activation (R-HSA-5673000)

Molecular Interaction Atlas (MIA) of This DOT

3 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 11 (MAP3K11).	[1]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Mitogen-activated protein kinase kinase kinase 11 (MAP3K11).	[8]
Sulfate	DMW0ZBF	Investigative	Sulfate affects the methylation of Mitogen-activated protein kinase kinase kinase 11 (MAP3K11).	[9]

7 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 11 (MAP3K11).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Mitogen-activated protein kinase kinase kinase 11 (MAP3K11).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mitogen-activated protein kinase kinase kinase 11 (MAP3K11).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mitogen-activated protein kinase kinase kinase 11 (MAP3K11).	[5]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of Mitogen-activated protein kinase kinase kinase 11 (MAP3K11).	[6]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Mitogen-activated protein kinase kinase kinase 11 (MAP3K11).	[7]
GW7604	DMCA4RM	Investigative	GW7604 increases the expression of Mitogen-activated protein kinase kinase kinase 11 (MAP3K11).	[6]

References

• [1] 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.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Gene expression profiles with activation of the estrogen receptor alpha-selective estrogen receptor modulator complex in breast cancer cells expressing wild-type estrogen receptor. Cancer Res. 2002 Aug 1;62(15):4419-26.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] 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.
• [9] Short-term airborne particulate matter exposure alters the epigenetic landscape of human genes associated with the mitogen-activated protein kinase network: a cross-sectional study. Environ Health. 2014 Nov 13;13:94. doi: 10.1186/1476-069X-13-94.