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mitogen-activated protein kinase kinase kinase 12

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Target not currently curated in GtoImmuPdb

Target id: 2072

Nomenclature: mitogen-activated protein kinase kinase kinase 12

Abbreviated Name: DLK

Family: LZK subfamily

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 859 12q13.13 MAP3K12 mitogen-activated protein kinase kinase kinase 12
Mouse - 888 15 F3 Map3k12 mitogen-activated protein kinase kinase kinase 12
Rat - 888 7q36 Map3k12 mitogen activated protein kinase kinase kinase 12
Previous and Unofficial Names Click here for help
dual leucine zipper kinase DLK | MAPK-upstream kinase | MEKK12 | MUK | ZPKP1
Database Links Click here for help
Alphafold Q12852 (Hs), Q60700 (Mm), Q63796 (Rn)
BRENDA 2.7.11.25
ChEMBL Target CHEMBL1908389 (Hs), CHEMBL4295854 (Mm)
Ensembl Gene ENSG00000139625 (Hs), ENSMUSG00000023050 (Mm), ENSRNOG00000015134 (Rn)
Entrez Gene 7786 (Hs), 26404 (Mm), 25579 (Rn)
Human Protein Atlas ENSG00000139625 (Hs)
KEGG Enzyme 2.7.11.25
KEGG Gene hsa:7786 (Hs), mmu:26404 (Mm), rno:25579 (Rn)
OMIM 600447 (Hs)
Pharos Q12852 (Hs)
RefSeq Nucleotide NM_006301 (Hs), NM_001163643 (Mm), NM_013055 (Rn)
RefSeq Protein NP_006292 (Hs), NP_001157115 (Mm), NP_037187 (Rn)
SynPHARM 85268 (in complex with compound 11 [PMID: 26431428])
85267 (in complex with GNE-3511)
UniProtKB Q12852 (Hs), Q60700 (Mm), Q63796 (Rn)
Wikipedia MAP3K12 (Hs)
Selected 3D Structures Click here for help
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:  9
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
IACS-52825 Small molecule or natural product Ligand has a PDB structure Hs Inhibition 8.9 pKd 5
⤷ pKd 8.9 (Kd 1.3x10-9 M) [5]
Description: Binding dissociation constant determined in the proprietary KINOMEscan KdELECT system
GNE-8505 Small molecule or natural product Hs Inhibition 9.8 pKi 3
⤷ pKi 9.8 (Ki 1.7x10-10 M) [3]
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 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition >9.3 pKi 9
⤷ pKi >9.3 (Ki <5x10-10 M) [9]
GDC-0134 Small molecule or natural product Hs Inhibition 8.4 pKi 1
⤷ pKi 8.4 (Ki 4.48x10-9 M) [1]
Description: Inhibition of human DLK catalytic domain activity (1 to 520 amino acids) in a TR-FRET assay.
compound 11 [PMID: 26431428] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.4 pKi 9
⤷ pKi 7.4 (Ki 4.2x10-8 M) [9]
compound 16d [Tao et al., 2009] Small molecule or natural product Hs Inhibition 9.0 pIC50 12
⤷ pIC50 9.0 (IC50 1x10-9 M) [12]
IACS-52825 Small molecule or natural product Ligand has a PDB structure Hs Inhibition 7.0 pIC50 5
⤷ pIC50 7.0 (IC50 1.07x10-7 M) [5]
Description: Inhibition of c-Jun phosphorylation in HEK293 cells stably expressing hDLK
CEP-1347 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.9 pIC50 11
⤷ pIC50 6.9 (IC50 1.14x10-7 M) [11]
Inhibitor Comments
Compound 16d was assayed for DLK inhibitory activity in the assay described in Maroney et al. (2001) [7].
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: 2,16
Key to terms and symbols Click column headers to sort
Target used in screen: DLK
Ligand Sp. Type Action Value Parameter
foretinib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.7 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.4 pKd
KW-2449 Small molecule or natural product 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
crizotinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.8 pKd
tozasertib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.7 pKd
JNJ-28312141 Small molecule or natural product Hs Inhibitor Inhibition 6.5 pKd
neratinib Small molecule or natural product Approved drug Hs Inhibitor Inhibition 6.4 pKd
SU-14813 Small molecule or natural product Hs Inhibitor Inhibition 6.3 pKd
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand 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 [4,8,10,14-15]. 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) [6]. DLK has been identified as a critical upstream regulator of JNK-mediated neurodegeneration (specifically JNK2/3-dependent proapoptotic signaling [4,10]) downstream of glutamate receptor hyper-activation [10]. Induced loss of DLK activity (genetic or pharmacological) attenuates the neuronal injury response and is neuroprotective [4,6,10,17]. 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 [1,11,13].

References

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1. Chen KX, Dong L, Estrada A, Gibbons P, Huestis M, Kellar T, Liu W, Lyssikatos JP, Ma C, Olivero A et al.. (2014) Biheteroaryl compounds and uses thereof. Patent number: WO2014177060A1. Assignee: F.Hoffmann-La Roche Ag, Genentech, Inc.. Priority date: 01/05/2013. Publication date: 06/11/2014.

2. 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]

3. 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.

4. 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]

5. Le K, Soth MJ, Cross JB, Liu G, Ray WJ, Ma J, Goodwani SG, Acton PJ, Buggia-Prevot V, Akkermans O et al.. (2023) Discovery of IACS-52825, a Potent and Selective DLK Inhibitor for Treatment of Chemotherapy-Induced Peripheral Neuropathy. J Med Chem, 66 (14): 9954-9971. [PMID:37436942]

6. 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]

7. 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]

8. 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]

9. 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]

10. 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]

11. 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]

12. 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

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

14. 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 USA, 110 (10): 4039-44. [PMID:23431164]

15. 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 USA, 110 (10): 4045-50. [PMID:23431148]

16. 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]

17. 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 01/09/2023. Accessed on 19/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2072.