mitogen-activated protein kinase kinase kinase 12 | LZK subfamily | IUPHAR/BPS Guide to PHARMACOLOGY

mitogen-activated protein kinase kinase kinase 12

Target id: 2072

Nomenclature: mitogen-activated protein kinase kinase kinase 12

Abbreviated Name: DLK

Family: LZK subfamily

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

   GtoImmuPdb view: OFF :     Currently no data for mitogen-activated protein kinase kinase kinase 12 in GtoImmuPdb

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 859 12q13 MAP3K12 mitogen-activated protein kinase kinase kinase 12
Mouse - 888 15 F3 Map3k12 mitogen-activated protein kinase kinase kinase 12
Rat - 888 7 q36 Map3k12 mitogen activated protein kinase kinase kinase 12
Previous and Unofficial Names
dual leucine zipper kinase DLK | MAPK-upstream kinase | MEKK12 | MUK | ZPKP1
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:  DLK in complex with inhibitor 2-((1-cyclopentyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)amino)isonicotinonitrile.
PDB Id:  5CEQ
Ligand:  compound 11 [PMID: 26431428]
Resolution:  1.91Å
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 Affinity Units Reference
GNE-8505 Hs Inhibition 9.8 pKi 2
pKi 9.8 (Ki 1.7x10-10 M) [2]
Description: In a TR-FRET assay measuring inhibition of a N-terminally GST-tagged DLK catalytic domain (amino acids 1-520) construct interaction with MKK4 substrate.
GNE-3511 Hs Inhibition >9.3 pKi 7
pKi >9.3 (Ki <5x10-10 M) [7]
compound 11 [PMID: 26431428] Hs Inhibition 7.4 pKi 7
pKi 7.4 (Ki 4.2x10-8 M) [7]
compound 16d [Tao et al., 2009] Hs Inhibition 9.0 pIC50 10
pIC50 9.0 (IC50 1x10-9 M) [10]
CEP-1347 Hs Inhibition 6.9 pIC50 9
pIC50 6.9 (IC50 1.14x10-7 M) [9]
Inhibitor Comments
Compound 16d was assayed for DLK inhibitory activity in the assay described in Maroney et al. (2001) [5].
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: 1,14

Key to terms and symbols Click column headers to sort
Target used in screen: DLK
Ligand Sp. Type Action Affinity Units
foretinib Hs Inhibitor Inhibition 7.7 pKd
NVP-TAE684 Hs Inhibitor Inhibition 7.4 pKd
KW-2449 Hs Inhibitor Inhibition 7.2 pKd
sunitinib Hs Inhibitor Inhibition 7.0 pKd
crizotinib Hs Inhibitor Inhibition 6.8 pKd
tozasertib Hs Inhibitor Inhibition 6.7 pKd
JNJ-28312141 Hs Inhibitor Inhibition 6.5 pKd
neratinib Hs Inhibitor Inhibition 6.4 pKd
SU-14813 Hs Inhibitor Inhibition 6.3 pKd
bosutinib Hs Inhibitor Inhibition 6.2 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
General Comments
Expression of DLK (MAP3K12) is enriched in neuronal tissue where it appears to act as an essential driver of the neuronal stress response [3,6,8,12-13]. It has been implicated in acute neuronal damage and in chronic neurodegeneration in animal models of neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS, motor neurone disease) [4]. DLK has been identified as a critical upstream regulator of JNK-mediated neurodegeneration (specifically JNK2/3-dependent proapoptotic signaling [3,8]) downstream of glutamate receptor hyper-activation [8]. Induced loss of DLK activity (genetic or pharmacological) attenuates the neuronal injury response and is neuroprotective [3-4,8,15]. Small molecule DLK inhibitors may offer a novel therapeutic strategy to prevent neuronal degeneration, and as a result development of tool compounds that can help elucidate DLK function is ongoing, with the goal of designing brain-penetrant, selective DLK therapeutics which have the potential to treat multiple neurodegenerative diseases [9,11].

References

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1. 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]

2. Estrada A, Liu W, Patel S, Siu M. (2017) 3-substituted pyrazoles and use as dlk inhibitors. Patent number: WO2014111496. Assignee: F. Hoffmann-La Roche Ag, Genentech, Inc.. Priority date: 18/01/2013. Publication date: 17/01/2017.

3. Ghosh AS, Wang B, Pozniak CD, Chen M, Watts RJ, Lewcock JW. (2011) DLK induces developmental neuronal degeneration via selective regulation of proapoptotic JNK activity. J. Cell Biol., 194 (5): 751-64. [PMID:21893599]

4. Le Pichon CE, Meilandt WJ, Dominguez S, Solanoy H, Lin H, Ngu H, Gogineni A, Sengupta Ghosh A, Jiang Z, Lee SH et al.. (2017) Loss of dual leucine zipper kinase signaling is protective in animal models of neurodegenerative disease. Sci Transl Med, 9 (403). [PMID:28814543]

5. 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]

6. Miller BR, Press C, Daniels RW, Sasaki Y, Milbrandt J, DiAntonio A. (2009) A dual leucine kinase-dependent axon self-destruction program promotes Wallerian degeneration. Nat. Neurosci., 12 (4): 387-9. [PMID:19287387]

7. Patel S, Harris SF, Gibbons P, Deshmukh G, Gustafson A, Kellar T, Lin H, Liu X, Liu Y, Liu Y et al.. (2015) Scaffold-Hopping and Structure-Based Discovery of Potent, Selective, And Brain Penetrant N-(1H-Pyrazol-3-yl)pyridin-2-amine Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12). J. Med. Chem., 58 (20): 8182-99. [PMID:26431428]

8. Pozniak CD, Sengupta Ghosh A, Gogineni A, Hanson JE, Lee SH, Larson JL, Solanoy H, Bustos D, Li H, Ngu H et al.. (2013) Dual leucine zipper kinase is required for excitotoxicity-induced neuronal degeneration. J. Exp. Med., 210 (12): 2553-67. [PMID:24166713]

9. Siu M, Sengupta Ghosh A, Lewcock JW. (2018) Dual Leucine Zipper Kinase Inhibitors for the Treatment of Neurodegeneration. J. Med. Chem., [Epub ahead of print]. [PMID:29863360]

10. Tao M, Park CH, Josef K, Hudkins RL. (2009) Regioselective synthesis of 2‐methyl‐2,5,6,11,12,13‐hexahydro 4H indazolo[5,4‐a]pyrrolo[3,4‐c]carbazole‐4‐ones. Journal of Heterocyclic Chemistry, 46 (6): 1185-1189. DOI: 10.1002/jhet.200

11. Villanueva MT. (2017) Neurodegenerative disease: DLK zips across neurodegeneration. Nat Rev Drug Discov, 16 (10): 678-679. [PMID:28935914]

12. Watkins TA, Wang B, Huntwork-Rodriguez S, Yang J, Jiang Z, Eastham-Anderson J, Modrusan Z, Kaminker JS, Tessier-Lavigne M, Lewcock JW. (2013) DLK initiates a transcriptional program that couples apoptotic and regenerative responses to axonal injury. Proc. Natl. Acad. Sci. U.S.A., 110 (10): 4039-44. [PMID:23431164]

13. Welsbie DS, Yang Z, Ge Y, Mitchell KL, Zhou X, Martin SE, Berlinicke CA, Hackler Jr L, Fuller J, Fu J et al.. (2013) Functional genomic screening identifies dual leucine zipper kinase as a key mediator of retinal ganglion cell death. Proc. Natl. Acad. Sci. U.S.A., 110 (10): 4045-50. [PMID:23431148]

14. 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]

15. Yin C, Huang GF, Sun XC, Guo Z, Zhang JH. (2017) DLK silencing attenuated neuron apoptosis through JIP3/MA2K7/JNK pathway in early brain injury after SAH in rats. Neurobiol. Dis., 103: 133-143. [PMID:28396258]

How to cite this page

LZK subfamily: mitogen-activated protein kinase kinase kinase 12. Last modified on 19/06/2018. Accessed on 15/11/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2072.