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mitogen-activated protein kinase kinase kinase 7

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Target id: 2082

Nomenclature: mitogen-activated protein kinase kinase kinase 7

Abbreviated Name: TAK1

Family: TAK1 subfamily

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 606 6q15 MAP3K7 mitogen-activated protein kinase kinase kinase 7
Mouse - 579 4 A5 Map3k7 mitogen-activated protein kinase kinase kinase 7
Rat - 606 5q21 Map3k7 mitogen activated protein kinase kinase kinase 7
Previous and Unofficial Names Click here for help
Map3k7 | TAK1 | TGF-beta activated kinase 1 | transforming growth factor beta-activated kinase 1
Database Links Click here for help
Alphafold O43318 (Hs), Q62073 (Mm), P0C8E4 (Rn)
BRENDA 2.7.11.25
ChEMBL Target CHEMBL5776 (Hs)
Ensembl Gene ENSG00000135341 (Hs), ENSMUSG00000028284 (Mm), ENSRNOG00000005724 (Rn)
Entrez Gene 6885 (Hs), 26409 (Mm), 313121 (Rn)
Human Protein Atlas ENSG00000135341 (Hs)
KEGG Enzyme 2.7.11.25
KEGG Gene hsa:6885 (Hs), mmu:26409 (Mm), rno:313121 (Rn)
OMIM 602614 (Hs)
Pharos O43318 (Hs)
RefSeq Nucleotide NM_003188 (Hs), NM_172688 (Mm), NM_001107920 (Rn)
RefSeq Protein NP_003179 (Hs), NP_766276 (Mm), NP_001101390 (Rn)
SynPHARM 81146 (in complex with 5Z-7-oxozeaenol)
84134 (in complex with compound 12 [PMID: 27448772])
81137 (in complex with NG-25)
84542 (in complex with Takinib)
UniProtKB O43318 (Hs), Q62073 (Mm), P0C8E4 (Rn)
Wikipedia MAP3K7 (Hs)
Selected 3D Structures Click here for help
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 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
compound 25 [PMID: 28038940] Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 8.6 pIC50 14
⤷ pIC50 8.6 (IC50 2.4x10-9 M) [14]
Description: In a biochemical enzyme activity assay.
RGB-286638 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.3 pIC50 4
⤷ pIC50 8.3 (IC50 5x10-9 M) [4]
Takinib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand 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] Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.0 pIC50 10
⤷ pIC50 8.0 (IC50 1.1x10-8 M) [10]
Description: In a biochemical assay.
compound 17d [PMID: 23099093] Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.9 pIC50 9
⤷ pIC50 7.9 (IC50 1.2x10-8 M) [9]
CEP-11981 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.8 pIC50 8
⤷ pIC50 7.8 (IC50 1.4x10-8 M) [8]
compound 5 [PMID: 28038940] Small molecule or natural product Ligand has a PDB structure Hs Inhibition 7.3 pIC50 14
⤷ pIC50 7.3 (IC50 5x10-8 M) [14]
Description: In a biochemical enzyme activity assay.
5Z-7-oxozeaenol Small molecule or natural product Primary target of this compound Ligand has a PDB structure 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 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure 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 Click here for help
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 Value Parameter
AST-487 Small molecule or natural product Hs Inhibitor Inhibition 8.8 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.5 pKd
JNJ-28312141 Small molecule or natural product Hs Inhibitor Inhibition 8.1 pKd
KW-2449 Small molecule or natural product Hs Inhibitor Inhibition 7.4 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.3 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.2 pKd
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 7.0 pKd
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.0 pKd
SU-14813 Small molecule or natural product Hs Inhibitor Inhibition 7.0 pKd
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand 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 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: 1,7
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 Small molecule or natural product Hs Inhibitor Inhibition 2.5 -1.0 -5.0
SU11652 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 3.5 4.0 -3.0
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 6.1 88.0 89.0
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.0 12.0 -0.5
JAK3 inhibitor VI Small molecule or natural product Hs Inhibitor Inhibition 9.7 10.0 -2.0
PKR inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 12.0 16.0 1.0
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 12.5 9.0 2.0
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 18.6
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 19.0 39.0 25.0
dovitinib Small molecule or natural product 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
Immuno Process:  T cell (activation)
Immuno Process:  B cell (activation)
Immuno Process:  Immune regulation
Immuno Process:  Cytokine production & signalling
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. 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 11/12/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2082.