Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7VFIFX)

• DOT Name: Mitogen-activated protein kinase kinase kinase 21 (MAP3K21)
• Synonyms: EC 2.7.11.25; Mitogen-activated protein kinase kinase kinase MLK4; Mixed lineage kinase 4
• Gene Name: MAP3K21
• UniProt ID: M3K21_HUMAN
• PDB ID: 4UYA
• EC Number: 2.7.11.25
• Pfam ID: PF07714 ; PF14604
• Sequence:
  MALRGAAGATDTPVSSAGGAPGGSASSSSTSSGGSASAGAGLWAALYDYEARGEDELSLR
  RGQLVEVLSQDAAVSGDEGWWAGQVQRRLGIFPANYVAPCRPAASPAPPPSRPSSPVHVA
  FERLELKELIGAGGFGQVYRATWQGQEVAVKAARQDPEQDAAAAAESVRREARLFAMLRH
  PNIIELRGVCLQQPHLCLVLEFARGGALNRALAAANAAPDPRAPGPRRARRIPPHVLVNW
  AVQIARGMLYLHEEAFVPILHRDLKSSNILLLEKIEHDDICNKTLKITDFGLAREWHRTT
  KMSTAGTYAWMAPEVIKSSLFSKGSDIWSYGVLLWELLTGEVPYRGIDGLAVAYGVAVNK
  LTLPIPSTCPEPFAKLMKECWQQDPHIRPSFALILEQLTAIEGAVMTEMPQESFHSMQDD
  WKLEIQQMFDELRTKEKELRSREEELTRAALQQKSQEELLKRREQQLAEREIDVLERELN
  ILIFQLNQEKPKVKKRKGKFKRSRLKLKDGHRISLPSDFQHKITVQASPNLDKRRSLNSS
  SSSPPSSPTMMPRLRAIQLTSDESNKTWGRNTVFRQEEFEDVKRNFKKKGCTWGPNSIQM
  KDRTDCKERIRPLSDGNSPWSTILIKNQKTMPLASLFVDQPGSCEEPKLSPDGLEHRKPK
  QIKLPSQAYIDLPLGKDAQRENPAEAESWEEAASANAATVSIEMTPTNSLSRSPQRKKTE
  SALYGCTVLLASVALGLDLRELHKAQAAEEPLPKEEKKKREGIFQRASKSRRSASPPTSL
  PSTCGEASSPPSLPLSSALGILSTPSFSTKCLLQMDSEDPLVDSAPVTCDSEMLTPDFCP
  TAPGSGREPALMPRLDTDCSVSRNLPSSFLQQTCGNVPYCASSKHRPSHHRRTMSDGNPT
  PTGATIISATGASALPLCPSPAPHSHLPREVSPKKHSTVHIVPQRRPASLRSRSDLPQAY
  PQTAVSQLAQTACVVGRPGPHPTQFLAAKERTKSHVPSLLDADVEGQSRDYTVPLCRMRS
  KTSRPSIYELEKEFLS
• Function: Negative regulator of TLR4 signaling. Does not activate JNK1/MAPK8 pathway, p38/MAPK14, nor ERK2/MAPK1 pathways.
• KEGG Pathway: MAPK sig.ling pathway (hsa04010)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Mitogen-activated protein kinase kinase kinase 21 (MAP3K21).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Mitogen-activated protein kinase kinase kinase 21 (MAP3K21).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Mitogen-activated protein kinase kinase kinase 21 (MAP3K21).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Mitogen-activated protein kinase kinase kinase 21 (MAP3K21).	[4]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Mitogen-activated protein kinase kinase kinase 21 (MAP3K21).	[5]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Mitogen-activated protein kinase kinase kinase 21 (MAP3K21).	[6]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Mitogen-activated protein kinase kinase kinase 21 (MAP3K21).	[7]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Mitogen-activated protein kinase kinase kinase 21 (MAP3K21).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Mitogen-activated protein kinase kinase kinase 21 (MAP3K21).	[8]

References

• [1] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [5] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [6] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [7] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [8] 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.
• [9] 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.