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mitogen-activated protein kinase 11

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 1500

Nomenclature: mitogen-activated protein kinase 11

Abbreviated Name: p38β

Family: p38 subfamily

Contents:

Gene and Protein Information Click here for help
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 Click here for help
SAPK2 | p38Beta | PRKM11
Database Links Click here for help
Alphafold Q15759 (Hs), Q9WUI1 (Mm)
BRENDA 2.7.11.24
ChEMBL Target CHEMBL3961 (Hs), CHEMBL4335 (Mm)
DrugBank Target Q15759 (Hs)
Ensembl Gene ENSG00000185386 (Hs), ENSMUSG00000053137 (Mm), ENSRNOG00000006984 (Rn)
Entrez Gene 5600 (Hs), 19094 (Mm), 689314 (Rn)
Human Protein Atlas ENSG00000185386 (Hs)
KEGG Enzyme 2.7.11.24
KEGG Gene hsa:5600 (Hs), mmu:19094 (Mm), rno:689314 (Rn)
OMIM 602898 (Hs)
Pharos Q15759 (Hs)
RefSeq Nucleotide NM_002751 (Hs), NM_011161 (Mm), NM_001109532 (Rn)
RefSeq Protein NP_002742 (Hs), NP_035291 (Mm), NP_001103002 (Rn)
UniProtKB Q15759 (Hs), Q9WUI1 (Mm)
Wikipedia MAPK11 (Hs)
Selected 3D Structures Click here for help
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 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
VX-702 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.8 pKd 9
⤷ pKd 7.8 (Kd 1.7x10-8 M) [9]
pamapimod Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 6.9 pKd 10
⤷ pKd 6.9 (Kd 1.2x10-7 M) [10]
Description: In a biochemical assay.
PH-797804 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 7.4 pKi 6
⤷ pKi 7.4 (Ki 4x10-8 M) [6]
SB203580 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.0 pKi 7
⤷ pKi 7.0 [7]
compound 4e [PMID: 35546685] Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 9.7 pIC50 2
⤷ pIC50 9.7 (IC50 2x10-10 M) [2]
ralimetinib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 9.0 pIC50 4
⤷ pIC50 9.0 (IC50 1x10-9 M) [4]
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 8.1 pIC50 16
⤷ pIC50 8.1 (IC50 7x10-9 M) [16]
Description: Inhibition of p38β2.
pexmetinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.6 pIC50 3
⤷ pIC50 7.6 (IC50 2.6x10-8 M) [3]
talmapimod 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 7.0 pIC50 19
⤷ pIC50 7.0 (IC50 9.8x10-8 M) [19]
TAK-715 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 6.7 pIC50 15
⤷ pIC50 6.7 (IC50 2x10-7 M) [15]
neflamapimod Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 6.7 pIC50 13
⤷ pIC50 6.7 (IC50 2.2x10-7 M) [13]
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: 5,21
Key to terms and symbols Click column headers to sort
Target used in screen: p38-beta
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
nilotinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 7.4 pKd
SB203580 Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 7.2 pKd
neflamapimod Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.1 pKd
PD-173955 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.0 pKd
sorafenib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.6 pKd
linifanib Small molecule or natural product Hs Inhibitor Inhibition 6.4 pKd
dasatinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.4 pKd
AST-487 Small molecule or natural product Hs Inhibitor Inhibition 6.4 pKd
foretinib Small molecule or natural product Ligand has a PDB structure 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: 1,8
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 Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 15.3
VX-702 Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 22.3
PD 169316 Small molecule or natural product Hs Inhibitor Inhibition 27.6 5.0 3.0
SB202190 Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 32.8 2.0 -1.0
p38 MAP kinase inhibitor III Small molecule or natural product Hs Inhibitor Inhibition 41.7 10.0 -2.0
sorafenib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 46.9
p38 MAP kinase inhibitor Small molecule or natural product Hs Inhibitor Inhibition 55.9 23.0 5.0
SB203580 Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 68.9 24.0 2.0
dasatinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 76.6
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure 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 [11-12,14,17-18,20]. 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

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. Armani E, Capaldi C, Bagnacani V, Saccani F, Aquino G, Puccini P, Facchinetti F, Martucci C, Moretto N, Villetti G et al.. (2022) Design, Synthesis, and Biological Characterization of Inhaled p38α/β MAPK Inhibitors for the Treatment of Lung Inflammatory Diseases. J Med Chem, 65 (10): 7170-7192. [PMID:35546685]

3. 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]

4. Bhattacharjee D, Bakar J, Chitnis SP, Sausville EL, Ashtekar KD, Mendelson BE, Long K, Smith JC, Heppner DE, Sheltzer JM. (2023) Inhibition of a lower potency target drives the anticancer activity of a clinical p38 inhibitor. Cell Chem Biol, 30 (10): 1211-1222.e5. [PMID:37827156]

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. 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]

7. 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]

8. 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]

9. 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]

10. 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]

11. 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]

12. 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]

13. 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]

14. 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]

15. 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]

16. 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]

17. 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]

18. 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]

19. 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]

20. 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]

21. 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 13/10/2023. Accessed on 16/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1500.