Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: Cot oncogene messenger RNA (MAP3K8 mRNA)
• Synonyms: Tumor progression locus 2 (mRNA); TPL-2 (mRNA); Serine/threonine-protein kinase cot (mRNA); Proto-oncogene c-Cot (mRNA); Mitogen-activated protein kinase kinase kinase 8 (mRNA); ESTF (mRNA); Cancer Osaka thyroid oncogene (mRNA); COT (mRNA)
• Gene Name: MAP3K8
• DTT Type: Literature-reported target; [1]
• BioChemical Class: mRNA target
• UniProt ID: M3K8_HUMAN
• TTD ID: T46700
• EC Number: EC 2.7.11.25
• Sequence:
  MEYMSTGSDNKEEIDLLIKHLNVSDVIDIMENLYASEEPAVYEPSLMTMCQDSNQNDERS
  KSLLLSGQEVPWLSSVRYGTVEDLLAFANHISNTAKHFYGQRPQESGILLNMVITPQNGR
  YQIDSDVLLIPWKLTYRNIGSDFIPRGAFGKVYLAQDIKTKKRMACKLIPVDQFKPSDVE
  IQACFRHENIAELYGAVLWGETVHLFMEAGEGGSVLEKLESCGPMREFEIIWVTKHVLKG
  LDFLHSKKVIHHDIKPSNIVFMSTKAVLVDFGLSVQMTEDVYFPKDLRGTEIYMSPEVIL
  CRGHSTKADIYSLGATLIHMQTGTPPWVKRYPRSAYPSYLYIIHKQAPPLEDIADDCSPG
  MRELIEASLERNPNHRPRAADLLKHEALNPPREDQPRCQSLDSALLERKRLLSRKELELP
  ENIADSSCTGSTEESEMLKRQRSLYIDLGALAGYFNLVRGPPTLEYG
• Function: Involved in the regulation of T-helper cell differentiation and IFNG expression in T-cells. Involved in mediating host resistance to bacterial infection through negative regulation of type I interferon (IFN) production. In vitro, activates MAPK/ERK pathway in response to IL1 in an IRAK1-independent manner, leading to up-regulation of IL8 and CCL4. Transduces CD40 and TNFRSF1A signals that activate ERK in B-cells and macrophages, and thus may play a role in the regulation of immunoglobulin production. May also play a role in the transduction of TNF signals that activate JNK and NF-kappa-B in some cell types. In adipocytes, activates MAPK/ERK pathway in an IKBKB-dependent manner in response to IL1B and TNF, but not insulin, leading to induction of lipolysis. Plays a role in the cell cycle. Isoform 1 shows some transforming activity, although it is much weaker than that of the activated oncogenic variant. Required for lipopolysaccharide (LPS)-induced, TLR4-mediated activation of the MAPK/ERK pathway in macrophages, thus being critical for production of the proinflammatory cytokine TNF-alpha (TNF) during immune responses.
• KEGG Pathway:
  MAPK signaling pathway (hsa04010)
  Toll-like receptor signaling pathway (hsa04620)
  T cell receptor signaling pathway (hsa04660)
  TNF signaling pathway (hsa04668)
• Reactome Pathway:
  MAP3K8 (TPL2)-dependent MAPK1/3 activation (R-HSA-5684264)
  CD28 dependent PI3K/Akt signaling (R-HSA-389357)

Molecular Interaction Atlas (MIA) of This DTT

9 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
8-chloro-quinoline-3-carbonitrile	DMFNUHQ	Discovery agent	N.A.	Investigative	[2]
ISIS 116359	DM280AE	Discovery agent	N.A.	Investigative	[3]
ISIS 116360	DMFEZHM	Discovery agent	N.A.	Investigative	[3]
ISIS 116361	DMWBQHS	Discovery agent	N.A.	Investigative	[3]
ISIS 116362	DM7M1UB	Discovery agent	N.A.	Investigative	[3]
ISIS 116363	DMXKAJP	Discovery agent	N.A.	Investigative	[3]
ISIS 116414	DM4Q3JO	Discovery agent	N.A.	Investigative	[3]
NSC-686549	DM0164B	Discovery agent	N.A.	Investigative	[4]
Tpl2 kinase inhibitor	DMHATCZ	Discovery agent	N.A.	Investigative	[1]

References

• [1] Inhibition of Tpl2 kinase and TNF-alpha production with 1,7-naphthyridine-3-carbonitriles: synthesis and structure-activity relationships. Bioorg Med Chem Lett. 2005 Dec 1;15(23):5288-92.
• [2] Pharmacologic inhibition of tpl2 blocks inflammatory responses in primary human monocytes, synoviocytes, and blood. J Biol Chem. 2007 Nov 16;282(46):33295-304.
• [3] US patent application no. 6,265,216, Antisense modulation of cot oncogene expression.
• [4] A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20523-8.