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mitogen-activated protein kinase kinase kinase 9

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Target not currently curated in GtoImmuPdb

Target id: 2084

Nomenclature: mitogen-activated protein kinase kinase kinase 9

Abbreviated Name: MLK1

Family: MLK subfamily

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1104 14q24.2 MAP3K9 mitogen-activated protein kinase kinase kinase 9
Mouse - 1077 12 D1 Map3k9 mitogen-activated protein kinase kinase kinase 9
Rat - 1077 6q24 Map3k9 mitogen-activated protein kinase kinase kinase 9
Previous and Unofficial Names Click here for help
MLK1 | PRKE1
Database Links Click here for help
Alphafold P80192 (Hs), Q3U1V8 (Mm)
BRENDA 2.7.11.25
ChEMBL Target CHEMBL2872 (Hs)
Ensembl Gene ENSG00000006432 (Hs), ENSMUSG00000042724 (Mm), ENSRNOG00000007271 (Rn)
Entrez Gene 4293 (Hs), 338372 (Mm), 500690 (Rn)
Human Protein Atlas ENSG00000006432 (Hs)
KEGG Enzyme 2.7.11.25
KEGG Gene hsa:4293 (Hs), mmu:338372 (Mm), rno:500690 (Rn)
OMIM 600136 (Hs)
Pharos P80192 (Hs)
RefSeq Nucleotide NM_033141 (Hs), NM_001174107 (Mm), NM_001100872 (Rn)
RefSeq Protein NP_149132 (Hs), NP_001167578 (Mm), NP_001094342 (Rn)
UniProtKB P80192 (Hs), Q3U1V8 (Mm)
Wikipedia MAP3K9 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of mixed-lineage kinase MLK1 complexed with compound 16
PDB Id:  3DTC
Resolution:  2.6Å
Species:  Human
References:  7
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
cerdulatinib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.3 pIC50 2
⤷ pIC50 8.3 (IC50 5x10-9 M) [2]
CEP-1347 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.4 – 9.0 pIC50 6,8,10
⤷ pIC50 7.4 – 9.0 (IC50 3.8x10-8 – 1x10-9 M) [6,8,10]
URMC-099 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.7 pIC50 6
⤷ pIC50 7.7 (IC50 1.9x10-8 M) [6]
compound 8e [PMID: 24432909] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.4 pIC50 10
⤷ pIC50 7.4 (IC50 3.8x10-8 M) [10]
GNE-3511 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.2 pIC50 9
⤷ pIC50 7.2 (IC50 6.78x10-8 M) [9]
P505-15 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.1 pIC50 3
⤷ pIC50 7.1 (IC50 8.8x10-8 M) [3]
apitolisib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.6 pIC50 11
⤷ pIC50 6.6 (IC50 2.32x10-7 M) [11]
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: 4,12
Key to terms and symbols Click column headers to sort
Target used in screen: MLK1
Ligand Sp. Type Action Value Parameter
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.5 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.4 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.0 pKd
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.8 pKd
pazopanib Small molecule or natural product Approved drug Hs Inhibitor Inhibition 6.5 pKd
tozasertib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.4 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.4 pKd
PD-173955 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.4 pKd
KW-2449 Small molecule or natural product Hs Inhibitor Inhibition 6.2 pKd
foretinib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.0 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: 1,5
Key to terms and symbols Click column headers to sort
Target used in screen: MLK1/MLK19MAP3K90
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition -0.4 -1.0 -1.0
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 0.4 1.0 1.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 0.4 1.0 0.0
Gö 6976 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 1.5 2.0 2.0
Cdk2 inhibitor IV Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 3.8 2.0 1.0
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.1 0.0 0.5
indirubin derivative E804 Small molecule or natural product Hs Inhibitor Inhibition 7.1 2.0 2.0
Cdk4 inhibitor Small molecule or natural product Hs Inhibitor Inhibition 7.6 85.0 31.0
aminopurvalanol A Small molecule or natural product Hs Inhibitor Inhibition 7.8 7.0 1.0
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 8.7 1.0 2.0
Displaying the top 10 most potent ligands  View all ligands in screen »

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. Coffey G, Betz A, DeGuzman F, Pak Y, Inagaki M, Baker DC, Hollenbach SJ, Pandey A, Sinha U. (2014) The novel kinase inhibitor PRT062070 (Cerdulatinib) demonstrates efficacy in models of autoimmunity and B-cell cancer. J Pharmacol Exp Ther, 351 (3): 538-48. [PMID:25253883]

3. Coffey G, DeGuzman F, Inagaki M, Pak Y, Delaney SM, Ives D, Betz A, Jia ZJ, Pandey A, Baker D et al.. (2012) Specific inhibition of spleen tyrosine kinase suppresses leukocyte immune function and inflammation in animal models of rheumatoid arthritis. J Pharmacol Exp Ther, 340 (2): 350-9. [PMID:22040680]

4. 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]

5. 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]

6. Goodfellow VS, Loweth CJ, Ravula SB, Wiemann T, Nguyen T, Xu Y, Todd DE, Sheppard D, Pollack S, Polesskaya O et al.. (2013) Discovery, synthesis, and characterization of an orally bioavailable, brain penetrant inhibitor of mixed lineage kinase 3. J Med Chem, 56 (20): 8032-48. [PMID:24044867]

7. Hudkins RL, Diebold JL, Tao M, Josef KA, Park CH, Angeles TS, Aimone LD, Husten J, Ator MA, Meyer SL et al.. (2008) Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: optimization, mixed-lineage kinase 1 crystallography, and oral in vivo activity in 1-methyl-4-phenyltetrahydropyridine models. J Med Chem, 51 (18): 5680-9. [PMID:18714982]

8. Maroney AC, Finn JP, Connors TJ, Durkin JT, Angeles T, Gessner G, Xu Z, Meyer SL, Savage MJ, Greene LA et al.. (2001) Cep-1347 (KT7515), a semisynthetic inhibitor of the mixed lineage kinase family. J Biol Chem, 276 (27): 25302-8. [PMID:11325962]

9. Patel S, Cohen F, Dean BJ, De La Torre K, Deshmukh G, Estrada AA, Ghosh AS, Gibbons P, Gustafson A, Huestis MP et al.. (2015) Discovery of dual leucine zipper kinase (DLK, MAP3K12) inhibitors with activity in neurodegeneration models. J Med Chem, 58 (1): 401-18. [PMID:25341110]

10. Siu M, Sengupta Ghosh A, Lewcock JW. (2018) Dual Leucine Zipper Kinase Inhibitors for the Treatment of Neurodegeneration. J Med Chem, 61 (18): 8078-8087. [PMID:29863360]

11. Sutherlin DP, Bao L, Berry M, Castanedo G, Chuckowree I, Dotson J, Folks A, Friedman L, Goldsmith R, Gunzner J et al.. (2011) Discovery of a potent, selective, and orally available class I phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) kinase inhibitor (GDC-0980) for the treatment of cancer. J Med Chem, 54 (21): 7579-87. [PMID:21981714]

12. 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]

How to cite this page

MLK subfamily: mitogen-activated protein kinase kinase kinase 9. Last modified on 19/06/2018. Accessed on 13/12/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2084.