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mitogen-activated protein kinase kinase kinase 8

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Target id: 2083

Nomenclature: mitogen-activated protein kinase kinase kinase 8

Abbreviated Name: Cot

Family: STE-unique family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 467 10p11.23 MAP3K8 mitogen-activated protein kinase kinase kinase 8
Mouse - 467 18 2.73 cM Map3k8 mitogen-activated protein kinase kinase kinase 8
Rat - 467 17q12.1 Map3k8 mitogen-activated protein kinase kinase kinase 8
Previous and Unofficial Names Click here for help
Cancer Osaka thyroid oncogene | ESTF | proto-oncogene c-COT | serine/threonine kinase (Tpl-2)
Database Links Click here for help
Alphafold P41279 (Hs), Q07174 (Mm), Q63562 (Rn)
BRENDA 2.7.11.25
ChEMBL Target CHEMBL4899 (Hs)
Ensembl Gene ENSG00000107968 (Hs), ENSMUSG00000024235 (Mm), ENSRNOG00000016378 (Rn)
Entrez Gene 1326 (Hs), 26410 (Mm), 116596 (Rn)
Human Protein Atlas ENSG00000107968 (Hs)
KEGG Enzyme 2.7.11.25
KEGG Gene hsa:1326 (Hs), mmu:26410 (Mm), rno:116596 (Rn)
OMIM 191195 (Hs)
Pharos P41279 (Hs)
RefSeq Nucleotide NM_001244134 (Hs), NM_007746 (Mm), NM_053847 (Rn)
RefSeq Protein NP_005195 (Hs), NP_031772 (Mm), NP_446299 (Rn)
UniProtKB P41279 (Hs), Q07174 (Mm), Q63562 (Rn)
Wikipedia MAP3K8 (Hs)
Enzyme Reaction Click here for help
EC Number: 2.7.11.25

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
MEK inhibitor II Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.3 pIC50 2
⤷ pIC50 7.3 (IC50 5x10-8 M) [2]
Tpl2 kinase inhibitor Small molecule or natural product Primary target of this compound Hs Inhibition 7.3 pIC50 4
⤷ pIC50 7.3 (IC50 5x10-8 M) [4]
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen Click here for help
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx

Reference: ...1
Key to terms and symbols Click column headers to sort
Target used in screen: nd/COT1(MAP3K8)
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
Src kinase inhibitor I Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 68.9
PDK1/Akt/Flt dual pathway inhibitor Small molecule or natural product Hs Inhibitor Inhibition 75.9
Tpl2 kinase inhibitor Small molecule or natural product Hs Inhibitor Inhibition 79.1
MEK inhibitor I Small molecule or natural product Hs Inhibitor Inhibition 79.8
Cdk1/5 inhibitor Small molecule or natural product Hs Inhibitor Inhibition 81.3
SU11274 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 82.9
casein kinase II inhibitor III Small molecule or natural product Hs Inhibitor Inhibition 83.0
Lck inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 83.3
fascaplysin Small molecule or natural product Hs Inhibitor Inhibition 84.9
PD98059 Small molecule or natural product Hs Inhibitor Inhibition 85.7
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
MAP3K8 (a.k.a. TPL2) is the primary regulator of ERK-mediated gene transcription downstream of multiple proinflammatory stimuli [3,6]. Its expression and activation are modulated by a range of inflammatory receptors, including TLRs, TNFR1, IL-1R1 and IL-1R2 [5], and it is able to amplify local inflammation by promoting the production of several proinflammatory cytokines (e.g. TNFα, IL-1β, IL-6 and IL-8) . Tpl2-deficient mice are protected from inflammatory and autoimmune diseases. Pharmacological inhibitors of MAP3K8 are therefore considered to offer potential to disrupt excessive inflammation and reduce the associated tissue damage in human chronic inflammatory and auto-iimmune diseases. Gilead Sciences have an orally bioavailable, selective MAP3K8 inhibitor in clinical development; GS-4875 (structure not disclosed) has been advanced to Phase 2 evaluation for ulcerative colitis (NCT04130919, primary completion date April 2021) [7].
Immuno Process Associations
Immuno Process:  T cell (activation)
Immuno Process:  Immune regulation
Immuno Process:  Cytokine production & signalling
Immuno Process:  Chemotaxis & migration
Immuno Process:  Cellular signalling

References

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1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1039-45. [PMID:22037377]

2. Fedorov O, Marsden B, Pogacic V, Rellos P, Müller S, Bullock AN, Schwaller J, Sundström M, Knapp S. (2007) A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc Natl Acad Sci USA, 104 (51): 20523-8. [PMID:18077363]

3. Gantke T, Sriskantharajah S, Ley SC. (2011) Regulation and function of TPL-2, an IκB kinase-regulated MAP kinase kinase kinase. Cell Res, 21 (1): 131-45. [PMID:21135874]

4. Gavrin LK, Green N, Hu Y, Janz K, Kaila N, Li HQ, Tam SY, Thomason JR, Gopalsamy A, Ciszewski G et al.. (2005) Inhibition of Tpl2 kinase and TNF-alpha production with 1,7-naphthyridine-3-carbonitriles: synthesis and structure-activity relationships. Bioorg Med Chem Lett, 15 (23): 5288-92. [PMID:16165349]

5. Senger K, Pham VC, Varfolomeev E, Hackney JA, Corzo CA, Collier J, Lau VWC, Huang Z, Hamidzhadeh K, Caplazi P et al.. (2017) The kinase TPL2 activates ERK and p38 signaling to promote neutrophilic inflammation. Sci Signal, 10 (475). [PMID:28420753]

6. Xu D, Matsumoto ML, McKenzie BS, Zarrin AA. (2018) TPL2 kinase action and control of inflammation. Pharmacol Res, 129: 188-193. [PMID:29183769]

7. Zarrin AA, Bao K, Lupardus P, Vucic D. (2021) Kinase inhibition in autoimmunity and inflammation. Nat Rev Drug Discov, 20 (1): 39-63. [PMID:33077936]

How to cite this page

STE-unique family: mitogen-activated protein kinase kinase kinase 8. Last modified on 08/01/2021. Accessed on 11/12/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2083.