mitogen-activated protein kinase 11 | p38 subfamily | IUPHAR Guide to IMMUNOPHARMACOLOGY

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mitogen-activated protein kinase 11

  Target has curated data in GtoImmuPdb

Target id: 1500

Nomenclature: mitogen-activated protein kinase 11

Abbreviated Name: p38β

Family: p38 subfamily

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

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 364 22q13.33 MAPK11 mitogen-activated protein kinase 11
Mouse - 364 15 E3 Mapk11 mitogen-activated protein kinase 11
Rat - 364 7q34 Mapk11 mitogen-activated protein kinase 11
Previous and Unofficial Names
SAPK2 | p38Beta | PRKM11
Database Links
BRENDA
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal Structure of Human Mitogen Activated Protein Kinase 11 (p38 beta) in complex with Nilotinib
PDB Id:  3GP0
Ligand:  nilotinib
Resolution:  1.9Å
Species:  Human
References: 
Enzyme Reaction
EC Number: 2.7.11.24

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 Value Parameter Reference
VX-702 Hs Inhibition 7.8 pKd 7
pKd 7.8 (Kd 1.7x10-8 M) [7]
pamapimod Hs Inhibition 6.9 pKd 8
pKd 6.9 (Kd 1.2x10-7 M) [8]
Description: In a biochemical assay.
PH-797804 Hs Inhibition 7.4 pKi 4
pKi 7.4 (Ki 4x10-8 M) [4]
SB203580 Hs Inhibition 7.0 pKi 5
pKi 7.0 [5]
doramapimod Hs Inhibition 8.1 pIC50 14
pIC50 8.1 (IC50 7x10-9 M) [14]
Description: Inhibition of p38β2.
pexmetinib Hs Inhibition 7.6 pIC50 2
pIC50 7.6 (IC50 2.6x10-8 M) [2]
talmapimod Hs Inhibition 7.0 pIC50 17
pIC50 7.0 (IC50 9.8x10-8 M) [17]
TAK-715 Hs Inhibition 6.7 pIC50 13
pIC50 6.7 (IC50 2x10-7 M) [13]
neflamapimod Hs Inhibition 6.7 pIC50 11
pIC50 6.7 (IC50 2.2x10-7 M) [11]
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: 3,19

Key to terms and symbols Click column headers to sort
Target used in screen: p38-beta
Ligand Sp. Type Action Value Parameter
doramapimod Hs Inhibitor Inhibition 8.1 pKd
nilotinib Hs Inhibitor Inhibition 7.4 pKd
SB203580 Hs Inhibitor Inhibition 7.2 pKd
neflamapimod Hs Inhibitor Inhibition 7.1 pKd
PD-173955 Hs Inhibitor Inhibition 7.0 pKd
sorafenib Hs Inhibitor Inhibition 6.6 pKd
linifanib Hs Inhibitor Inhibition 6.4 pKd
dasatinib Hs Inhibitor Inhibition 6.4 pKd
AST-487 Hs Inhibitor Inhibition 6.4 pKd
foretinib 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
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: SAPK2b/P38b(MAPK11)
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
nilotinib Hs Inhibitor Inhibition 15.3
VX-702 Hs Inhibitor Inhibition 22.3
PD 169316 Hs Inhibitor Inhibition 27.6 5.0 3.0
SB202190 Hs Inhibitor Inhibition 32.8 2.0 -1.0
p38 MAP kinase inhibitor III Hs Inhibitor Inhibition 41.7 10.0 -2.0
sorafenib Hs Inhibitor Inhibition 46.9
p38 MAP kinase inhibitor Hs Inhibitor Inhibition 55.9 23.0 5.0
SB203580 Hs Inhibitor Inhibition 68.9 24.0 2.0
dasatinib Hs Inhibitor Inhibition 76.6
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 78.5 56.0 24.0
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 [9-10,12,15-16,18]. 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.
Immuno Process Associations
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 2 GO processes
GO:0071347 cellular response to interleukin-1 IDA
GO:2001184 positive regulation of interleukin-12 secretion IMP

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. Bachegowda L, Morrone K, Winski SL, Mantzaris I, Bartenstein M, Ramachandra N, Giricz O, Sukrithan V, Nwankwo G, Shahnaz S et al.. (2016) Pexmetinib: A Novel Dual Inhibitor of Tie2 and p38 MAPK with Efficacy in Preclinical Models of Myelodysplastic Syndromes and Acute Myeloid Leukemia. Cancer Res., 76 (16): 4841-4849. [PMID:27287719]

3. 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]

4. Devadas B, Selness SR, Xing L, Madsen HM, Marrufo LD, Shieh H, Messing DM, Yang JZ, Morgan HM, Anderson GD et al.. (2011) Substituted N-aryl-6-pyrimidinones: a new class of potent, selective, and orally active p38 MAP kinase inhibitors. Bioorg. Med. Chem. Lett., 21 (13): 3856-60. [PMID:21620699]

5. Eyers PA, Craxton M, Morrice N, Cohen P, Goedert M. (1998) Conversion of SB 203580-insensitive MAP kinase family members to drug-sensitive forms by a single amino-acid substitution. Chem. Biol., 5 (6): 321-8. [PMID:9653550]

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, Kuglstatter A, Lou Y, Soth MJ. (2010) Selective p38alpha inhibitors clinically evaluated for the treatment of chronic inflammatory disorders. J. Med. Chem., 53 (6): 2345-53. [PMID:19950901]

8. 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]

9. 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]

10. 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]

11. Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT et al.. (2008) A quantitative analysis of kinase inhibitor selectivity. Nat. Biotechnol., 26 (1): 127-32. [PMID:18183025]

12. 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]

13. Miwatashi S, Arikawa Y, Kotani E, Miyamoto M, Naruo K, Kimura H, Tanaka T, Asahi S, Ohkawa S. (2005) Novel inhibitor of p38 MAP kinase as an anti-TNF-alpha drug: discovery of N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (TAK-715) as a potent and orally active anti-rheumatoid arthritis agent. J Med Chem, 48 (19): 5966-79. [PMID:16162000]

14. 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]

15. 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]

16. 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]

17. Tan X, Tester RW, Luedtke GR, Chakravarty S, Mavunkel BJ, Perumattam JJ, Lu Q, Nashashibi I, Jung J, Hu J et al.. (2010) Design and synthesis of piperazine-indole p38 alpha MAP kinase inhibitors with improved pharmacokinetic profiles. Bioorg. Med. Chem. Lett., 20 (3): 828-31. [PMID:20071169]

18. 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]

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]

How to cite this page

p38 subfamily: mitogen-activated protein kinase 11. Last modified on 30/10/2019. Accessed on 03/08/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=1500.