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mitogen-activated protein kinase 9

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Target id: 1497

Nomenclature: mitogen-activated protein kinase 9

Abbreviated Name: JNK2

Family: JNK subfamily

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 424 5q35.3 MAPK9 mitogen-activated protein kinase 9
Mouse - 423 11 B1.2-B1.3 Mapk9 mitogen-activated protein kinase 9
Rat - 423 10q21 Mapk9 mitogen-activated protein kinase 9
Previous and Unofficial Names Click here for help
c-Jun N-terminal kinase 2 | JNK-55 | JNK/SAPK alpha | Jun kinase | MAP kinase 9 | PRKM9 | SAPK1A | SAPK-alpha | Stress-activated protein kinase 1a | stress activated protein kinase alpha II | stress-activated protein kinase JNK2
Database Links Click here for help
Alphafold P45984 (Hs), Q9WTU6 (Mm), P49186 (Rn)
BRENDA 2.7.11.24
ChEMBL Target CHEMBL4179 (Hs), CHEMBL2034797 (Mm)
Ensembl Gene ENSG00000050748 (Hs), ENSMUSG00000020366 (Mm), ENSRNOG00000002823 (Rn)
Entrez Gene 5601 (Hs), 26420 (Mm), 50658 (Rn)
Human Protein Atlas ENSG00000050748 (Hs)
KEGG Enzyme 2.7.11.24
KEGG Gene hsa:5601 (Hs), mmu:26420 (Mm), rno:50658 (Rn)
OMIM 602896 (Hs)
Pharos P45984 (Hs)
RefSeq Nucleotide NM_001135044 (Hs), NM_207692 (Mm), NM_017322 (Rn)
RefSeq Protein NP_001128516 (Hs), NP_997575 (Mm), NP_001157143 (Mm), NP_001157144 (Mm), NP_058657 (Mm), NP_059018 (Rn)
UniProtKB P45984 (Hs), Q9WTU6 (Mm), P49186 (Rn)
Wikipedia MAPK9 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal Structure of JNK2
PDB Id:  3E7O
Resolution:  2.14Å
Species:  Human
References:  15
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of JNK2 complexed with BIRB796
PDB Id:  3NPC
Ligand:  doramapimod
Resolution:  2.35Å
Species:  Human
References:  10
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 7.8 pKd 7
⤷ pKd 7.8 (Kd 1.6x10-8 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 8.4 pKi 18
⤷ pKi 8.4 (Ki 4x10-9 M) [18]
tanzisertib Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.1 pIC50 12
⤷ pIC50 8.1 (IC50 7x10-9 M) [12]
JNK-IN-8 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.7 pIC50 22
⤷ pIC50 7.7 (IC50 1.87x10-8 M) [22]
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 3
⤷ pIC50 7.4 (IC50 4x10-8 M) [3]
RGB-286638 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.4 pIC50 4
⤷ pIC50 7.4 (IC50 4x10-8 M) [4]
compound 20 [PMID: 30998356] Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.2 pIC50 13
⤷ pIC50 7.2 (IC50 5.9x10-8 M) [13]
Description: Measuring in vitro enzyme inhibitory activity.
YL5084 Small molecule or natural product Click here for species-specific activity table Hs Irreversible inhibition 7.2 pIC50 11
⤷ pIC50 7.2 (IC50 7x10-8 M) [11]
BOS172722 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.1 pIC50 20
⤷ pIC50 7.1 (IC50 7.6x10-8 M) [20]
JNK inhibitor IX Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 6.5 pIC50 2
⤷ pIC50 6.5 (IC50 3.162x10-7 M) [2]
compound 25c [PMID: 36649216] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.0 pIC50 16
⤷ pIC50 5.0 (IC50 9.27x10-6 M) [16]
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: 5,19
Key to terms and symbols Click column headers to sort
Target used in screen: JNK2
Ligand Sp. Type Action Value Parameter
doramapimod Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.1 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.3 pKd
AST-487 Small molecule or natural product Hs Inhibitor Inhibition 7.3 pKd
SB203580 Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 6.9 pKd
KW-2449 Small molecule or natural product Hs Inhibitor Inhibition 6.6 pKd
linifanib Small molecule or natural product Hs Inhibitor Inhibition 6.6 pKd
fedratinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.6 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.6 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.5 pKd
GSK-1838705A Small molecule or natural product Hs Inhibitor Inhibition 6.3 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: JNK2α2/JNK2
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
p38 MAP kinase inhibitor Small molecule or natural product Hs Inhibitor Inhibition 6.1 7.0 -10.0
JNK inhibitor VIII Small molecule or natural product Hs Inhibitor Inhibition 6.4 -1.0 -11.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 12.4 5.0 -11.0
p38 MAP kinase inhibitor III Small molecule or natural product Hs Inhibitor Inhibition 31.1 39.0 -6.0
JAK inhibitor I Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 31.1 64.0 17.0
JNK inhibitor IX Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 33.9 58.0 74.0
SP600125 Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 36.4 26.0 -6.0
indirubin derivative E804 Small molecule or natural product Hs Inhibitor Inhibition 44.3 43.0 30.0
PD 169316 Small molecule or natural product Hs Inhibitor Inhibition 45.5 68.0 59.0
PKR inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 45.8 71.0 16.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
Experimental evidence suggests that JNK2 is important in T-cell differentiation [8,14,17,21]. Signalling through JNK2, but not JNK1 has been associated with a loss of Treg cell function and an increase in pathogenic CD4+ T effector cell function, and the exacerbation of asthma-like immunopathology in mice [9].
Immuno Process Associations
Immuno Process:  Immune regulation
Immuno Process:  Cellular signalling
Immuno Process:  Chemotaxis & migration
Immuno Process:  Cytokine production & signalling

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. Angell RM, Atkinson FL, Brown MJ, Chuang TT, Christopher JA, Cichy-Knight M, Dunn AK, Hightower KE, Malkakorpi S, Musgrave JR et al.. (2007) N-(3-Cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)amides as potent, selective, inhibitors of JNK2 and JNK3. Bioorg Med Chem Lett, 17 (5): 1296-301. [PMID:17194588]

3. 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]

4. Cirstea D, Hideshima T, Santo L, Eda H, Mishima Y, Nemani N, Hu Y, Mimura N, Cottini F, Gorgun G et al.. (2013) Small-molecule multi-targeted kinase inhibitor RGB-286638 triggers P53-dependent and -independent anti-multiple myeloma activity through inhibition of transcriptional CDKs. Leukemia, 27 (12): 2366-75. [PMID:23807770]

5. 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]

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. Jang WY, Lee JY, Lee ST, Jun do Y, Kim YH. (2014) Inhibition of JNK2 and JNK3 by JNK inhibitor IX induces prometaphase arrest-dependent apoptotic cell death in human Jurkat T cells. Biochem Biophys Res Commun, 452 (3): 845-51. [PMID:25218503]

9. Joetham A, Schedel M, Takeda K, Jia Y, Ashino S, Dakhama A, Lluis A, Okamoto M, Gelfand EW. (2014) JNK2 regulates the functional plasticity of naturally occurring T regulatory cells and the enhancement of lung allergic responses. J Immunol, 193 (5): 2238-47. [PMID:25070841]

10. Kuglstatter A, Ghate M, Tsing S, Villaseñor AG, Shaw D, Barnett JW, Browner MF. (2010) X-ray crystal structure of JNK2 complexed with the p38alpha inhibitor BIRB796: insights into the rational design of DFG-out binding MAP kinase inhibitors. Bioorg Med Chem Lett, 20 (17): 5217-20. [PMID:20655210]

11. 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]

12. 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]

13. 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]

14. Sabapathy K, Hu Y, Kallunki T, Schreiber M, David JP, Jochum W, Wagner EF, Karin M. (1999) JNK2 is required for efficient T-cell activation and apoptosis but not for normal lymphocyte development. Curr Biol, 9 (3): 116-25. [PMID:10021384]

15. Shaw D, Wang SM, Villaseñor AG, Tsing S, Walter D, Browner MF, Barnett J, Kuglstatter A. (2008) The crystal structure of JNK2 reveals conformational flexibility in the MAP kinase insert and indicates its involvement in the regulation of catalytic activity. J Mol Biol, 383 (4): 885-93. [PMID:18801372]

16. 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]

17. Su B, Jacinto E, Hibi M, Kallunki T, Karin M, Ben-Neriah Y. (1994) JNK is involved in signal integration during costimulation of T lymphocytes. Cell, 77 (5): 727-36. [PMID:8205621]

18. 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]

19. 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]

20. 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]

21. Yang DD, Conze D, Whitmarsh AJ, Barrett T, Davis RJ, Rincón M, Flavell RA. (1998) Differentiation of CD4+ T cells to Th1 cells requires MAP kinase JNK2. Immunity, 9 (4): 575-85. [PMID:9806643]

22. 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 9. Last modified on 06/06/2023. Accessed on 18/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=1497.