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mitogen-activated protein kinase 8

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Target id: 1496

Nomenclature: mitogen-activated protein kinase 8

Abbreviated Name: JNK1

Family: JNK subfamily

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 427 10q11.22 MAPK8 mitogen-activated protein kinase 8
Mouse - 384 14 B Mapk8 mitogen-activated protein kinase 8
Rat - 411 16p16 Mapk8 mitogen-activated protein kinase 8
Previous and Unofficial Names Click here for help
c-jun NH2-terminal kinase | c-Jun N-terminal kinase 1 | JNK | JNK-46 | MAP kinase 8 | PRKM8 | SAPK gamma | SAPK1C | Stress-activated protein kinase 1c | stress-activated protein kinase JNK1
Database Links Click here for help
Alphafold P45983 (Hs), Q91Y86 (Mm), P49185 (Rn)
BRENDA 2.7.11.24
ChEMBL Target CHEMBL2276 (Hs), CHEMBL1795174 (Mm), CHEMBL5718 (Rn)
Ensembl Gene ENSG00000107643 (Hs), ENSMUSG00000021936 (Mm), ENSRNOG00000020155 (Rn)
Entrez Gene 5599 (Hs), 26419 (Mm), 116554 (Rn)
Human Protein Atlas ENSG00000107643 (Hs)
KEGG Enzyme 2.7.11.24
KEGG Gene hsa:5599 (Hs), mmu:26419 (Mm), rno:116554 (Rn)
OMIM 601158 (Hs)
Pharos P45983 (Hs)
RefSeq Nucleotide NM_002750 (Hs), NM_016700 (Mm), NM_053829 (Rn)
RefSeq Protein NP_002741 (Hs), NP_057909 (Mm), NP_446281 (Rn)
SynPHARM 78578 (in complex with SP600125)
UniProtKB P45983 (Hs), Q91Y86 (Mm), P49185 (Rn)
Wikipedia MAPK8 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Jnk1 complexed with a bis-anilino-pyrrolopyrimidine inhibitor.
PDB Id:  3ELJ
Resolution:  1.8Å
Species:  Human
References:  3
Enzyme Reaction Click here for help
EC Number: 2.7.11.24

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
pamapimod Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 6.7 pKd 7
⤷ pKd 6.7 (Kd 1.9x10-7 M) [7]
Description: In a biochemical assay.
JNK inhibitor VIII Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.7 pKi 16
⤷ pKi 8.7 (Ki 2x10-9 M) [16]
JNK-IN-8 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.3 pIC50 19
⤷ pIC50 8.3 (IC50 4.7x10-9 M) [19]
compound 20 [PMID: 30998356] Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.5 pIC50 14
⤷ pIC50 7.5 (IC50 3.2x10-8 M) [14]
Description: Measuring in vitro enzyme inhibitory activity.
SP600125 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.4 pIC50 2
⤷ pIC50 7.4 (IC50 4x10-8 M) [2]
tanzisertib Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.2 pIC50 13
⤷ pIC50 7.2 (IC50 6.1x10-8 M) [13]
compound 35 [PMID: 23916259] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.0 pIC50 9
⤷ pIC50 7.0 (IC50 9.2x10-8 M) [9]
BOS172722 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.0 pIC50 18
⤷ pIC50 7.0 (IC50 9.2x10-8 M) [18]
JNK inhibitor 9l Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.0 pIC50 8
⤷ pIC50 7.0 (IC50 9.9x10-8 M) [8]
GNE-3511 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.9 pIC50 11
⤷ pIC50 6.9 (IC50 1.29x10-7 M) [11]
SU-3327 Small molecule or natural product Hs Inhibition 6.2 pIC50 5
⤷ pIC50 6.2 (IC50 7x10-7 M) [5]
Description: Biochemical inhibition in a LanthaScreen kinase activity assay.
compound 11 [PMID: 26431428] Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.0 pIC50 12
⤷ pIC50 6.0 (IC50 1.004x10-6 M) [12]
YL5084 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.7 pIC50 10
⤷ pIC50 5.7 (IC50 2.173x10-6 M) [10]
compound 25c [PMID: 36649216] Small molecule or natural product Click here for species-specific activity table Hs Inhibition <5.0 pIC50 15
⤷ pIC50 <5.0 (IC50 >1x10-5 M) [15]
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: 4,17
Key to terms and symbols Click column headers to sort
Target used in screen: JNK1
Ligand Sp. Type Action Value Parameter
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.0 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.4 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.8 pKd
GSK-1838705A Small molecule or natural product Hs Inhibitor Inhibition 6.7 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.7 pKd
fedratinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.6 pKd
nilotinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.3 pKd
AST-487 Small molecule or natural product Hs Inhibitor Inhibition 6.3 pKd
KW-2449 Small molecule or natural product Hs Inhibitor Inhibition 6.2 pKd
JNJ-28312141 Small molecule or natural product Hs Inhibitor Inhibition 6.1 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: 1,6
Key to terms and symbols Click column headers to sort
Target used in screen: JNK1α1/JNK1
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
JNK inhibitor VIII Small molecule or natural product Hs Inhibitor Inhibition 28.1 -16.0 -6.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 28.8 -12.0 -20.0
Cdk2 inhibitor IV Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 51.1 44.0 -11.0
JAK inhibitor I Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 73.7 32.0 9.0
PD 174265 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 73.7 94.0 76.0
aloisine Small molecule or natural product Hs Inhibitor Inhibition 74.5 105.0 103.0
BAY 11-7082 Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 74.7 115.0 96.0
PDK1/Akt/Flt dual pathway inhibitor Small molecule or natural product Hs Inhibitor Inhibition 78.3 114.0 83.0
Gö 6976 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 78.7 88.0 31.0
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 78.8 88.0 84.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
By regulating AP-1 transcriptional activity in response to cytokine activation, JNK1 contributes to the production of immunomodulators such as RANTES, IL-8 and GM-CSF .
Immuno Process Associations
Immuno Process:  Immune regulation
Immuno Process:  Cytokine production & signalling
Immuno Process:  Cellular signalling
Immuno Process:  Inflammation

References

Show »

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. Bennett BL, Sasaki DT, Murray BW, O'Leary EC, Sakata ST, Xu W, Leisten JC, Motiwala A, Pierce S, Satoh Y et al.. (2001) SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci USA, 98 (24): 13681-6. [PMID:11717429]

3. Chamberlain SD, Redman AM, Wilson JW, Deanda F, Shotwell JB, Gerding R, Lei H, Yang B, Stevens KL, Hassell AM et al.. (2009) Optimization of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidine IGF-1R tyrosine kinase inhibitors towards JNK selectivity. Bioorg Med Chem Lett, 19 (2): 360-4. [PMID:19071018]

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. De SK, Stebbins JL, Chen LH, Riel-Mehan M, Machleidt T, Dahl R, Yuan H, Emdadi A, Barile E, Chen V et al.. (2009) Design, synthesis, and structure-activity relationship of substrate competitive, selective, and in vivo active triazole and thiadiazole inhibitors of the c-Jun N-terminal kinase. J Med Chem, 52 (7): 1943-52. [PMID:19271755]

6. 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]

7. Goldstein DM, Soth M, Gabriel T, Dewdney N, Kuglstatter A, Arzeno H, Chen J, Bingenheimer W, Dalrymple SA, Dunn J et al.. (2011) Discovery of 6-(2,4-difluorophenoxy)-2-[3-hydroxy-1-(2-hydroxyethyl)propylamino]-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (pamapimod) and 6-(2,4-difluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (R1487) as orally bioavailable and highly selective inhibitors of p38α mitogen-activated protein kinase. J Med Chem, 54 (7): 2255-65. [PMID:21375264]

8. Kamenecka T, Jiang R, Song X, Duckett D, Chen W, Ling YY, Habel J, Laughlin JD, Chambers J, Figuera-Losada M et al.. (2010) Synthesis, biological evaluation, X-ray structure, and pharmacokinetics of aminopyrimidine c-jun-N-terminal kinase (JNK) inhibitors. J Med Chem, 53 (1): 419-31. [PMID:19947601]

9. Li B, Cociorva OM, Nomanbhoy T, Weissig H, Li Q, Nakamura K, Liyanage M, Zhang MC, Shih AY, Aban A et al.. (2013) Hit-to-lead optimization and kinase selectivity of imidazo[1,2-a]quinoxalin-4-amine derived JNK1 inhibitors. Bioorg Med Chem Lett, 23 (18): 5217-22. [PMID:23916259]

10. Lu W, Liu Y, Gao Y, Geng Q, Gurbani D, Li L, Ficarro SB, Meyer CJ, Sinha D, You I et al.. (2023) Development of a Covalent Inhibitor of c-Jun N-Terminal Protein Kinase (JNK) 2/3 with Selectivity over JNK1. J Med Chem, 66 (5): 3356-3371. [PMID:36826833]

11. 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]

12. 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]

13. Plantevin Krenitsky V, Nadolny L, Delgado M, Ayala L, Clareen SS, Hilgraf R, Albers R, Hegde S, D'Sidocky N, Sapienza J et al.. (2012) Discovery of CC-930, an orally active anti-fibrotic JNK inhibitor. Bioorg Med Chem Lett, 22 (3): 1433-8. [PMID:22244937]

14. Riggs JR, Elsner J, Cashion D, Robinson D, Tehrani L, Nagy M, Fultz KE, Krishna Narla R, Peng X, Tran T et al.. (2019) Design and Optimization Leading to an Orally Active TTK Protein Kinase Inhibitor with Robust Single Agent Efficacy. J Med Chem, 62 (9): 4401-4410. [PMID:30998356]

15. Shuai W, Bu F, Zhu Y, Wu Y, Xiao H, Pan X, Zhang J, Sun Q, Wang G, Ouyang L. (2023) Discovery of Novel Indazole Chemotypes as Isoform-Selective JNK3 Inhibitors for the Treatment of Parkinson's Disease. J Med Chem, 66 (2): 1273-1300. [PMID:36649216]

16. Szczepankiewicz BG, Kosogof C, Nelson LT, Liu G, Liu B, Zhao H, Serby MD, Xin Z, Liu M, Gum RJ et al.. (2006) Aminopyridine-based c-Jun N-terminal kinase inhibitors with cellular activity and minimal cross-kinase activity. J Med Chem, 49 (12): 3563-80. [PMID:16759099]

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. Woodward HL, Innocenti P, Cheung KJ, Hayes A, Roberts J, Henley AT, Faisal A, Mak GW, Box G, Westwood IM et al.. (2018) Introduction of a Methyl Group Curbs Metabolism of Pyrido[3,4- d]pyrimidine Monopolar Spindle 1 (MPS1) Inhibitors and Enables the Discovery of the Phase 1 Clinical Candidate N2-(2-Ethoxy-4-(4-methyl-4 H-1,2,4-triazol-3-yl)phenyl)-6-methyl- N8-neopentylpyrido[3,4- d]pyrimidine-2,8-diamine (BOS172722). J Med Chem, 61 (18): 8226-8240. [PMID:30199249]

19. Zhang T, Inesta-Vaquera F, Niepel M, Zhang J, Ficarro SB, Machleidt T, Xie T, Marto JA, Kim N, Sim T et al.. (2012) Discovery of potent and selective covalent inhibitors of JNK. Chem Biol, 19 (1): 140-54. [PMID:22284361]

How to cite this page

JNK subfamily: mitogen-activated protein kinase 8. Last modified on 06/06/2023. Accessed on 18/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=1496.