mitogen-activated protein kinase kinase kinase 9 | MLK subfamily | IUPHAR/BPS Guide to PHARMACOLOGY

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mitogen-activated protein kinase kinase kinase 9

Target not currently curated in GtoImmuPdb

Target id: 2084

Nomenclature: mitogen-activated protein kinase kinase kinase 9

Abbreviated Name: MLK1

Family: MLK 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 - 1118 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
MLK1 | PRKE1
Database Links
BRENDA
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures
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
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 Value Parameter Reference
cerdulatinib Hs Inhibition 8.3 pIC50 2
pIC50 8.3 (IC50 5x10-9 M) [2]
CEP-1347 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 Hs Inhibition 7.7 pIC50 6
pIC50 7.7 (IC50 1.9x10-8 M) [6]
compound 8e [PMID: 24432909] Hs Inhibition 7.4 pIC50 10
pIC50 7.4 (IC50 3.8x10-8 M) [10]
GNE-3511 Hs Inhibition 7.2 pIC50 9
pIC50 7.2 (IC50 6.78x10-8 M) [9]
P505-15 Hs Inhibition 7.1 pIC50 3
pIC50 7.1 (IC50 8.8x10-8 M) [3]
apitolisib Hs Inhibition 6.6 pIC50 11
pIC50 6.6 (IC50 2.32x10-7 M) [11]
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: 4,12

Key to terms and symbols Click column headers to sort
Target used in screen: MLK1
Ligand Sp. Type Action Value Parameter
lestaurtinib Hs Inhibitor Inhibition 8.5 pKd
tamatinib Hs Inhibitor Inhibition 8.4 pKd
staurosporine Hs Inhibitor Inhibition 8.0 pKd
midostaurin Hs Inhibitor Inhibition 7.8 pKd
pazopanib Hs Inhibitor Inhibition 6.5 pKd
tozasertib Hs Inhibitor Inhibition 6.4 pKd
PD-173955 Hs Inhibitor Inhibition 6.4 pKd
NVP-TAE684 Hs Inhibitor Inhibition 6.4 pKd
KW-2449 Hs Inhibitor Inhibition 6.2 pKd
foretinib 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
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 Hs Inhibitor Inhibition -0.4 -1.0 -1.0
midostaurin Hs Inhibitor Inhibition 0.4 1.0 1.0
K-252a Hs Inhibitor Inhibition 0.4 1.0 0.0
Gö 6976 Hs Inhibitor Inhibition 1.5 2.0 2.0
Cdk2 inhibitor IV Hs Inhibitor Inhibition 3.8 2.0 1.0
staurosporine Hs Inhibitor Inhibition 7.1 0.0 0.5
indirubin derivative E804 Hs Inhibitor Inhibition 7.1 2.0 2.0
Cdk4 inhibitor Hs Inhibitor Inhibition 7.6 85.0 31.0
aminopurvalanol A Hs Inhibitor Inhibition 7.8 7.0 1.0
SB 218078 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 19/11/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2084.