Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTJQT60)

• DTT Name: TGF-beta-activated kinase 1 (MAP3K7)
• Synonyms: Transforming growth factor-beta-activated kinase 1; TAK1; Mitogen-activated protein kinase kinase kinase 7
• Gene Name: MAP3K7
• DTT Type: Literature-reported target; [1]
• BioChemical Class: Kinase
• UniProt ID: M3K7_HUMAN
• TTD ID: T04361
• EC Number: EC 2.7.11.25
• Sequence:
  MSTASAASSSSSSSAGEMIEAPSQVLNFEEIDYKEIEVEEVVGRGAFGVVCKAKWRAKDV
  AIKQIESESERKAFIVELRQLSRVNHPNIVKLYGACLNPVCLVMEYAEGGSLYNVLHGAE
  PLPYYTAAHAMSWCLQCSQGVAYLHSMQPKALIHRDLKPPNLLLVAGGTVLKICDFGTAC
  DIQTHMTNNKGSAAWMAPEVFEGSNYSEKCDVFSWGIILWEVITRRKPFDEIGGPAFRIM
  WAVHNGTRPPLIKNLPKPIESLMTRCWSKDPSQRPSMEEIVKIMTHLMRYFPGADEPLQY
  PCQYSDEGQSNSATSTGSFMDIASTNTSNKSDTNMEQVPATNDTIKRLESKLLKNQAKQQ
  SESGRLSLGASRGSSVESLPPTSEGKRMSADMSEIEARIAATTAYSKPKRGHRKTASFGN
  ILDVPEIVISGNGQPRRRSIQDLTVTGTEPGQVSSRSSSPSVRMITTSGPTSEKPTRSHP
  WTPDDSTDTNGSDNSIPMAYLTLDHQLQPLAPCPNSKESMAVFEQHCKMAQEYMKVQTEI
  ALLLQRKQELVAELDQDEKDQQNTSRLVQEHKKLLDENKSLSTYYQQCKKQLEVIRSQQQ
  KRQGTS
• Function: Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signal transduction of TRAF6, various cytokines including interleukin-1 (IL-1), transforming growth factor-beta (TGFB), TGFB-related factors like BMP2 and BMP4, toll-like receptors (TLR), tumor necrosis factor receptor CD40 and B-cell receptor (BCR). Ceramides are also able to activate MAP3K7/TAK1. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K1/MEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs, c-jun N-terminal kinases (JNKs) and I-kappa-B kinase complex (IKK). Both p38 MAPK and JNK pathways control the transcription factors activator protein-1 (AP-1), while nuclear factor-kappa B is activated by IKK. MAP3K7 activates also IKBKB and MAPK8/JNK1 in response to TRAF6 signaling and mediates BMP2-induced apoptosis. In osmotic stress signaling, plays a major role in the activation of MAPK8/JNK1, but not that of NF-kappa-B. Promotes TRIM5 capsid-specific restriction activity. Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway.
• KEGG Pathway:
  MAPK signaling pathway (hsa04010)
  NF-kappa B signaling pathway (hsa04064)
  Autophagy - animal (hsa04140)
  AMPK signaling pathway (hsa04152)
  Wnt signaling pathway (hsa04310)
  Osteoclast differentiation (hsa04380)
  Adherens junction (hsa04520)
  Neutrophil extracellular trap formation (hsa04613)
  Toll-like receptor signaling pathway (hsa04620)
  NOD-like receptor signaling pathway (hsa04621)
  RIG-I-like receptor signaling pathway (hsa04622)
  IL-17 signaling pathway (hsa04657)
  T cell receptor signaling pathway (hsa04660)
  TNF signaling pathway (hsa04668)
  Alcoholic liver disease (hsa04936)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Yersinia infection (hsa05135)
  Leishmaniasis (hsa05140)
  Toxoplasmosis (hsa05145)
  Hepatitis B (hsa05161)
  Measles (hsa05162)
  Herpes simplex virus 1 infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Human immunodeficiency virus 1 infection (hsa05170)
  Coronavirus disease - COVID-19 (hsa05171)
  Lipid and atherosclerosis (hsa05417)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  NOD1/2 Signaling Pathway (R-HSA-168638)
  FCERI mediated NF-kB activation (R-HSA-2871837)
  Ca2+ pathway (R-HSA-4086398)
  TAK1 activates NFkB by phosphorylation and activation of IKKs complex (R-HSA-445989)
  Interleukin-1 signaling (R-HSA-446652)
  activated TAK1 mediates p38 MAPK activation (R-HSA-450302)
  JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 (R-HSA-450321)
  TNFR1-induced NFkappaB signaling pathway (R-HSA-5357956)
  CLEC7A (Dectin-1) signaling (R-HSA-5607764)
  TRAF6 mediated induction of TAK1 complex (R-HSA-937072)
  Activation of NF-kappaB in B cells (R-HSA-1169091)

Molecular Interaction Atlas (MIA) of This DTT

3 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AZ-TAK1	DMD4LGN	Mantle cell lymphoma	2A85.5	Investigative	[1]
NG-25	DMC48D9	Discovery agent	N.A.	Investigative	[2]
PMID23099093C17d	DMWS7O9	Discovery agent	N.A.	Investigative	[3]

References

• [1] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2082).
• [2] Discovery of type II inhibitors of TGFbeta-activated kinase 1 (TAK1) and mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2). J Med Chem. 2015 Jan 8;58(1):183-96.
• [3] Synthesis and structure-activity relationships of a novel series of pyrimidines as potent inhibitors of TBK1/IKKepsilon kinases. Bioorg Med Chem Lett. 2012 Dec 1;22(23):7169-73.