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mitogen-activated protein kinase 12

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 1501

Nomenclature: mitogen-activated protein kinase 12

Abbreviated Name: p38γ

Family: p38 subfamily

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 367 22q13.33 MAPK12 mitogen-activated protein kinase 12
Mouse - 367 15 E3 Mapk12 mitogen-activated protein kinase 12
Rat - 367 7q34 Mapk12 mitogen-activated protein kinase 12
Previous and Unofficial Names Click here for help
ERK5 | SAPK3 | extracellular signal-regulated kinase 6 | MAP kinase 12 | MAP kinase p38 gamma | MAPK 12 | mitogen-activated protein kinase p38 gamma | SAP kinase-3 | stress-activated protein kinase 3 | ERK6 | p38gamma | PRKM12
Database Links Click here for help
BRENDA
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  PHOSPHORYLATED MAP KINASE P38-GAMMA
PDB Id:  1CM8
Resolution:  2.4Å
Species:  Human
References:  2
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
doramapimod Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.5 pIC50 9
pIC50 7.5 (IC50 3x10-8 M) [9]
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: 4,13

Key to terms and symbols Click column headers to sort
Target used in screen: p38-gamma
Ligand Sp. Type Action Value Parameter
doramapimod Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.5 pKd
AST-487 Small molecule or natural product Hs Inhibitor Inhibition 7.5 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.4 pKd
lestaurtinib Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 6.4 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.4 pKd
foretinib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.4 pKd
SB203580 Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 5.8 pKd
linifanib Small molecule or natural product Hs Inhibitor Inhibition 5.7 pKd
ruboxistaurin Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition <5.5 pKd
erlotinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition <5.5 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: 1,5

Key to terms and symbols Click column headers to sort
Target used in screen: SAPK3/P38g
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
VEGF receptor tyrosine kinase inhibitor III Small molecule or natural product Hs Inhibitor Inhibition 61.9
DNA-PK inhibitor III Small molecule or natural product Hs Inhibitor Inhibition 78.7 110.0 102.0
Gö 6983 Small molecule or natural product Hs Inhibitor Inhibition 84.8 100.0 100.0
p38 MAP kinase inhibitor Small molecule or natural product Hs Inhibitor Inhibition 85.2 96.0 69.0
GSK-3 inhibitor X Small molecule or natural product Hs Inhibitor Inhibition 85.2 94.0 92.0
Gö 6976 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 85.8 61.0 61.0
isogranulatimide Small molecule or natural product Hs Inhibitor Inhibition 85.9 95.0 87.0
PP1 analog II Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 86.6 100.0 98.0
GSK-3 inhibitor XIII Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 86.8 103.0 91.0
GSK-3 inhibitor XIII Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 86.8 103.0 91.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
p38 MAP kinases are ubiquitous, highly conserved enzymes which regulate the production of proinflammatory mediators (such as TNFα and IL-1) in response to inflammatory cytokines or environmental stress [6-8,10-12]. They are essential for normal immune and inflammatory responses, but are also involved in many other cellular processes such as regulating the cell cycle and cytoskeletal remodelling.

Pharmacological inhibition of p38 MAP kinases reduces inflammatory cytokine synthesis, making these enzymes validated and extensively pursued drug targets for autoimmune and inflammatory diseases, including arthritis and other joint diseases, septic shock, myocardial injury and neuroinflammation. A number of pan-p38 MAP kinase inhibitors and isoform selective inhibitors have been evaluated in clinical trials, although none have yet reached the clinic.
General Comments
SARS-CoV-2: p38 MAP kinase activity is reported to be upregulated by SARS-CoV-2 infection in vitro [3]. siRNA-mediated knockdown of MAPK12 (p38γ) in A549-ACE2 cells significantly reduces SARS-CoV-2 replication, without reducing cell viability.

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. Bellon S, Fitzgibbon MJ, Fox T, Hsiao HM, Wilson KP. (1999) The structure of phosphorylated p38gamma is monomeric and reveals a conserved activation-loop conformation. Structure, 7 (9): 1057-65. [PMID:10508788]

3. Bouhaddou M, Memon D, Meyer B, White KM, Rezelj VV, Marrero MC, Polacco BJ, Melnyk JE, Ulferts S, Kaake RM. (2020) The Global Phosphorylation Landscape of SARS-CoV-2 Infection. Cell, Article Online Now. DOI: 10.1016/j.cell.2020.06.034

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. Han J, Jiang Y, Li Z, Kravchenko VV, Ulevitch RJ. (1997) Activation of the transcription factor MEF2C by the MAP kinase p38 in inflammation. Nature, 386 (6622): 296-9. [PMID:9069290]

7. Han J, Lee JD, Bibbs L, Ulevitch RJ. (1994) A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science, 265 (5173): 808-11. [PMID:7914033]

8. Lee JC, Kumar S, Griswold DE, Underwood DC, Votta BJ, Adams JL. (2000) Inhibition of p38 MAP kinase as a therapeutic strategy. Immunopharmacology, 47 (2-3): 185-201. [PMID:10878289]

9. Moffett K, Konteatis Z, Nguyen D, Shetty R, Ludington J, Fujimoto T, Lee KJ, Chai X, Namboodiri H, Karpusas M et al.. (2011) Discovery of a novel class of non-ATP site DFG-out state p38 inhibitors utilizing computationally assisted virtual fragment-based drug design (vFBDD). Bioorg. Med. Chem. Lett., 21 (23): 7155-65. [PMID:22014550]

10. Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, Cobb MH. (2001) Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr. Rev., 22 (2): 153-83. [PMID:11294822]

11. Raingeaud J, Gupta S, Rogers JS, Dickens M, Han J, Ulevitch RJ, Davis RJ. (1995) Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J. Biol. Chem., 270 (13): 7420-6. [PMID:7535770]

12. Wang XZ, Ron D. (1996) Stress-induced phosphorylation and activation of the transcription factor CHOP (GADD153) by p38 MAP Kinase. Science, 272 (5266): 1347-9. [PMID:8650547]

13. 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

p38 subfamily: mitogen-activated protein kinase 12. Last modified on 30/06/2020. Accessed on 25/11/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1501.