mitogen-activated protein kinase kinase kinase 7 | TAK1 subfamily | IUPHAR Guide to IMMUNOPHARMACOLOGY

Top ▲

mitogen-activated protein kinase kinase kinase 7

  Target has curated data in GtoImmuPdb

Target id: 2082

Nomenclature: mitogen-activated protein kinase kinase kinase 7

Abbreviated Name: TAK1

Family: TAK1 subfamily

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 579 6q15 MAP3K7 mitogen-activated protein kinase kinase kinase 7
Mouse - 579 4 A5 Map3k7 mitogen-activated protein kinase kinase kinase 7
Rat - 606 5 q21 Map3k7 mitogen activated protein kinase kinase kinase 7
Previous and Unofficial Names
TAK1 | Map3k7 | TGF-beta activated kinase 1 | transforming growth factor beta-activated kinase 1
Database Links
BRENDA
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Structural Basis for the Interaction of TAK1 Kinase with its Activating Protein TAB1
PDB Id:  2EVA
Resolution:  2.0Å
Species:  Human
References:  3
Image of receptor 3D structure from RCSB PDB
Description:  Irreversible Inhibition of TAK1 Kinase by 5Z-7-Oxozeaenol
PDB Id:  4GS6
Resolution:  2.2Å
Species:  Human
References:  18
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of type II inhibitor NG-25 bound to TAK1-TAB1 chimeric protein.
PDB Id:  4O91
Ligand:  NG-25
Resolution:  2.39Å
Species:  Human
References:  15
Image of receptor 3D structure from RCSB PDB
Description:  The structure of MAP2K7in complex with 5Z-7-oxozeaenol.
PDB Id:  3WZU
Ligand:  5Z-7-oxozeaenol
Resolution:  3.1Å
Species:  Human
References:  13
Enzyme Reaction
EC Number: 2.7.11.25

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Parameter Reference
compound 25 [PMID: 28038940] Hs Inhibition 8.6 pIC50 14
pIC50 8.6 (IC50 2.4x10-9 M) [14]
Description: In a biochemical enzyme activity assay.
RGB-286638 Hs Inhibition 8.3 pIC50 4
pIC50 8.3 (IC50 5x10-9 M) [4]
Takinib Hs Inhibition 8.0 pIC50 16
pIC50 8.0 (IC50 9.5x10-9 M) [16]
Description: In vitro kinase activity assay, measuring phosphorylation of a peptide substrate by a purified recombinant TAK1 kinase domain fused to TAB1 c-terminal domain.
compound 12 [PMID: 27448772] Hs Inhibition 8.0 pIC50 10
pIC50 8.0 (IC50 1.1x10-8 M) [10]
Description: In a biochemical assay.
compound 17d [PMID: 23099093] Hs Inhibition 7.9 pIC50 9
pIC50 7.9 (IC50 1.2x10-8 M) [9]
CEP-11981 Hs Inhibition 7.8 pIC50 8
pIC50 7.8 (IC50 1.4x10-8 M) [8]
compound 5 [PMID: 28038940] Hs Inhibition 7.3 pIC50 14
pIC50 7.3 (IC50 5x10-8 M) [14]
Description: In a biochemical enzyme activity assay.
5Z-7-oxozeaenol Hs Inhibition 6.5 – 8.1 pIC50 2,18
pIC50 6.5 – 8.1 (IC50 3x10-7 – 9x10-9 M) [2,18]
Description: Assayed using TAK1/TAB1 (TAK1-binding protein 1) fusion protein for full enzymatic activity. Inhibition of kinase activity.
NG-25 Hs Inhibition 6.8 pIC50 15
pIC50 6.8 (IC50 1.49x10-7 M) [15]
Inhibitor Comments
5Z-7-oxozeaenol inhibits the ATPase activity of a TAK1/TAB1 fusion protein with an IC50 of 14nM [18].
DiscoveRx KINOMEscan® screen
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 6,17

Key to terms and symbols Click column headers to sort
Target used in screen: TAK1
Ligand Sp. Type Action Affinity Parameter
AST-487 Hs Inhibitor Inhibition 8.8 pKd
lestaurtinib Hs Inhibitor Inhibition 8.5 pKd
JNJ-28312141 Hs Inhibitor Inhibition 8.1 pKd
KW-2449 Hs Inhibitor Inhibition 7.4 pKd
tamatinib Hs Inhibitor Inhibition 7.3 pKd
staurosporine Hs Inhibitor Inhibition 7.2 pKd
sunitinib Hs Inhibitor Inhibition 7.0 pKd
bosutinib Hs Inhibitor Inhibition 7.0 pKd
SU-14813 Hs Inhibitor Inhibition 7.0 pKd
midostaurin Hs Inhibitor Inhibition 6.9 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen
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: 1,7

Key to terms and symbols Click column headers to sort
Target used in screen: TAK1/TAK1
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
K-252a Hs Inhibitor Inhibition 2.5 -1.0 -5.0
SU11652 Hs Inhibitor Inhibition 3.5 4.0 -3.0
SB 218078 Hs Inhibitor Inhibition 6.1 88.0 89.0
staurosporine Hs Inhibitor Inhibition 8.0 12.0 -0.5
JAK3 inhibitor VI Hs Inhibitor Inhibition 9.7 10.0 -2.0
PKR inhibitor Hs Inhibitor Inhibition 12.0 16.0 1.0
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 12.5 9.0 2.0
sunitinib Hs Inhibitor Inhibition 18.6
midostaurin Hs Inhibitor Inhibition 19.0 39.0 25.0
dovitinib Hs Inhibitor Inhibition 19.3
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
TAK1 (MAP3K7) mediates signaling downstream of multiple cytokine receptors and is functionally important in mitogen, immune, and inflammatory signaling pathways [5,11]. This enzyme is the subject of drug discovery programmes for inflammatory disorders, as well as for cancer [10-11]. Scarneo et al. (2018) have validated TAK1 inhibition as a therapeutic strategy that can effectively inhibit macrophage TNF secretion using genetic and pharmacological techniques [12].
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 5 GO processes
GO:0002223 stimulatory C-type lectin receptor signaling pathway TAS
GO:0002726 positive regulation of T cell cytokine production IMP
GO:0002755 MyD88-dependent toll-like receptor signaling pathway TAS
GO:0002756 MyD88-independent toll-like receptor signaling pathway TAS
GO:0070423 nucleotide-binding oligomerization domain containing signaling pathway TAS
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 2 GO processes
GO:0002726 positive regulation of T cell cytokine production IMP
GO:0050870 positive regulation of T cell activation IC
Immuno Process:  B cell (activation)
GO Annotations:  Associated to 1 GO processes
GO:0002726 positive regulation of T cell cytokine production IMP
Immuno Process:  Immune regulation
GO Annotations:  Associated to 8 GO processes
GO:0002223 stimulatory C-type lectin receptor signaling pathway TAS
GO:0002726 positive regulation of T cell cytokine production IMP
GO:0002755 MyD88-dependent toll-like receptor signaling pathway TAS
GO:0002756 MyD88-independent toll-like receptor signaling pathway TAS
GO:0038095 Fc-epsilon receptor signaling pathway TAS
GO:0050852 T cell receptor signaling pathway TAS
GO:0050870 positive regulation of T cell activation IC
GO:0070423 nucleotide-binding oligomerization domain containing signaling pathway TAS
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 3 GO processes
GO:0002726 positive regulation of T cell cytokine production IMP
GO:0032743 positive regulation of interleukin-2 production IMP
GO:0070498 interleukin-1-mediated signaling pathway TAS
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 1 GO processes
GO:0050870 positive regulation of T cell activation IC
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 7 GO processes
GO:0002223 stimulatory C-type lectin receptor signaling pathway TAS
GO:0002755 MyD88-dependent toll-like receptor signaling pathway TAS
GO:0002756 MyD88-independent toll-like receptor signaling pathway TAS
GO:0038095 Fc-epsilon receptor signaling pathway TAS
GO:0050852 T cell receptor signaling pathway TAS
GO:0050870 positive regulation of T cell activation IC
GO:0070423 nucleotide-binding oligomerization domain containing signaling pathway TAS

References

Show »

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. Barf T, Kaptein A. (2012) Irreversible protein kinase inhibitors: balancing the benefits and risks. J. Med. Chem., 55 (14): 6243-62. [PMID:22621397]

3. Brown K, Vial SC, Dedi N, Long JM, Dunster NJ, Cheetham GM. (2005) Structural basis for the interaction of TAK1 kinase with its activating protein TAB1. J. Mol. Biol., 354 (5): 1013-20. [PMID:16289117]

4. Cirstea D, Hideshima T, Santo L, Eda H, Mishima Y, Nemani N, Hu Y, Mimura N, Cottini F, Gorgun G et al.. (2013) Small-molecule multi-targeted kinase inhibitor RGB-286638 triggers P53-dependent and -independent anti-multiple myeloma activity through inhibition of transcriptional CDKs. Leukemia, 27 (12): 2366-75. [PMID:23807770]

5. Dai L, Aye Thu C, Liu XY, Xi J, Cheung PC. (2012) TAK1, more than just innate immunity. IUBMB Life, 64 (10): 825-34. [PMID:22941947]

6. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1046-51. [PMID:22037378]

7. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem. J., 451 (2): 313-28. [PMID:23398362]

8. Hudkins RL, Becknell NC, Zulli AL, Underiner TL, Angeles TS, Aimone LD, Albom MS, Chang H, Miknyoczki SJ, Hunter K et al.. (2012) Synthesis and biological profile of the pan-vascular endothelial growth factor receptor/tyrosine kinase with immunoglobulin and epidermal growth factor-like homology domains 2 (VEGF-R/TIE-2) inhibitor 11-(2-methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-indazolo[5,4-a]pyrrolo[3,4-c]carbazol-4-one (CEP-11981): a novel oncology therapeutic agent. J. Med. Chem., 55 (2): 903-13. [PMID:22148921]

9. McIver EG, Bryans J, Birchall K, Chugh J, Drake T, Lewis SJ, Osborne J, Smiljanic-Hurley E, Tsang W, Kamal A et al.. (2012) Synthesis and structure-activity relationships of a novel series of pyrimidines as potent inhibitors of TBK1/IKKε kinases. Bioorg. Med. Chem. Lett., 22 (23): 7169-73. [PMID:23099093]

10. Muraoka T, Ide M, Morikami K, Irie M, Nakamura M, Miura T, Kamikawa T, Nishihara M, Kashiwagi H. (2016) Discovery of a potent and highly selective transforming growth factor β receptor-associated kinase 1 (TAK1) inhibitor by structure based drug design (SBDD). Bioorg. Med. Chem., 24 (18): 4206-17. [PMID:27448772]

11. Sakurai H. (2012) Targeting of TAK1 in inflammatory disorders and cancer. Trends Pharmacol. Sci., 33 (10): 522-30. [PMID:22795313]

12. Scarneo SA, Mansourati A, Eibschutz LS, Totzke J, Roques JR, Loiselle D, Carlson D, Hughes P, Haystead TAJ. (2018) Genetic and pharmacological validation of TAK1 inhibition in macrophages as a therapeutic strategy to effectively inhibit TNF secretion. Sci Rep, 8 (1): 17058. [PMID:30451876]

13. Sogabe Y, Matsumoto T, Hashimoto T, Kirii Y, Sawa M, Kinoshita T. (2015) 5Z-7-Oxozeaenol covalently binds to MAP2K7 at Cys218 in an unprecedented manner. Bioorg. Med. Chem. Lett., 25 (3): 593-6. [PMID:25529738]

14. Tan L, Gurbani D, Weisberg EL, Jones DS, Rao S, Singer WD, Bernard FM, Mowafy S, Jenney A, Du G et al.. (2017) Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. Bioorg. Med. Chem., 25 (4): 1320-1328. [PMID:28038940]

15. Tan L, Nomanbhoy T, Gurbani D, Patricelli M, Hunter J, Geng J, Herhaus L, Zhang J, Pauls E, Ham Y et al.. (2015) Discovery of Type II Inhibitors of TGFβ-Activated Kinase 1 (TAK1) and Mitogen-Activated Protein Kinase Kinase Kinase Kinase 2 (MAP4K2). J. Med. Chem., 58 (1): 183-96. [PMID:25075558]

16. Totzke J, Gurbani D, Raphemot R, Hughes PF, Bodoor K, Carlson DA, Loiselle DR, Bera AK, Eibschutz LS, Perkins MM et al.. (2017) Takinib, a Selective TAK1 Inhibitor, Broadens the Therapeutic Efficacy of TNF-α Inhibition for Cancer and Autoimmune Disease. Cell Chem Biol, 24 (8): 1029-1039.e7. [PMID:28820959]

17. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem. Biol., 17 (11): 1241-9. [PMID:21095574]

18. Wu J, Powell F, Larsen NA, Lai Z, Byth KF, Read J, Gu RF, Roth M, Toader D, Saeh JC et al.. (2013) Mechanism and In Vitro Pharmacology of TAK1 Inhibition by (5Z)-7-Oxozeaenol. ACS Chem. Biol., 8 (3): 643-50. [PMID:23272696]

How to cite this page

TAK1 subfamily: mitogen-activated protein kinase kinase kinase 7. Last modified on 26/11/2018. Accessed on 25/03/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2082.