mitogen-activated protein kinase 1 | ERK subfamily | IUPHAR Guide to IMMUNOPHARMACOLOGY

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mitogen-activated protein kinase 1

  Target has curated data in GtoImmuPdb

Target id: 1495

Nomenclature: mitogen-activated protein kinase 1

Abbreviated Name: ERK2

Family: ERK 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 - 360 22q11.2 MAPK1 mitogen-activated protein kinase 1
Mouse - 358 16 Mapk1 mitogen-activated protein kinase 1
Rat - 358 11q23 Mapk1 mitogen activated protein kinase 1
Previous and Unofficial Names
ERT1 | extracellular signal-regulated kinase 2 | extracellular-signal-regulated kinase 1 | MAP kinase 1 | MAP kinase 2 | MAP kinase isoform p42 | MAPK 1 | MAPK 2 | p42mapk | PRKM1 | PRKM2
Database Links
BRENDA
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Complex of ERK2 with norathyriol
PDB Id:  3SA0
Resolution:  1.59Å
Species:  Human
References:  10
Image of receptor 3D structure from RCSB PDB
Description:  X-ray structure of ERK2 in complex with the small molecule inhibitor FR180204
PDB Id:  1TVO
Ligand:  ERK inhibitor II
Resolution:  2.5Å
Species:  Human
References:  14
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 Affinity Parameter Reference
ERK inhibitor III Hs Binding 4.9 pKd 5
pKd 4.9 (Kd 1.3x10-5 M) [5]
Description: Measuring binding of the compound to human ERK2 in a fluorescence spectroscopy experiment, where fluorescence quenching is indicative of a binding interaction
VTX-11e Hs Inhibition >8.7 pKi 2
pKi >8.7 (Ki <2x10-9 M) [2]
ERK inhibitor II Hs Inhibition 6.8 pKi 14
pKi 6.8 (Ki 1.4x10-7 M) [14]
ulixertinib Hs Inhibition >9.5 pIC50 18
pIC50 >9.5 (IC50 <3x10-10 M) [18]
Description: Biochemical assay determination
SCH772984 Hs Inhibition 8.4 – 9.0 pIC50 12
pIC50 9.0 (IC50 1x10-9 M) [12]
pIC50 8.4 (IC50 4x10-9 M) [12]
compound 27 [PMID: 29775310] Hs Inhibition 8.5 pIC50 8
pIC50 8.5 (IC50 3x10-9 M) [8]
ravoxertinib Hs Inhibition 7.8 – 8.5 pIC50 3-4
pIC50 7.8 – 8.5 (IC50 1.55x10-8 – 3.1x10-9 M) [3-4]
MK-8353 Hs Inhibition 8.1 pIC50 13
pIC50 8.1 (IC50 8.8x10-9 M) [13]
Description: Measuring inhibition of activated ERK2 in a IMAP kinase assay.
CHIR-99021 Hs Inhibition <5.0 pIC50 16
pIC50 <5.0 (IC50 >1x10-5 M) [16]
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: 6,19

Key to terms and symbols Click column headers to sort
Target used in screen: ERK2
Ligand Sp. Type Action Affinity Parameter
NVP-TAE684 Hs Inhibitor Inhibition 6.5 pKd
erlotinib Hs Inhibitor Inhibition <5.5 pKd
A-674563 Hs Inhibitor Inhibition <5.5 pKd
GSK690693 Hs Inhibitor Inhibition <5.5 pKd
ruboxistaurin Hs Inhibitor Inhibition <5.5 pKd
SB203580 Hs Inhibitor Inhibition <5.5 pKd
gefitinib Hs Inhibitor Inhibition <5.5 pKd
masitinib Hs Inhibitor Inhibition <5.5 pKd
crizotinib Hs Inhibitor Inhibition <5.5 pKd
linifanib 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
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: 1,7

Key to terms and symbols Click column headers to sort
Target used in screen: MAPK2/ERK2(MAPK1)
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
PKR inhibitor Hs Inhibitor Inhibition 28.8 4.0 -3.0
K-252a Hs Inhibitor Inhibition 48.0 5.0 -3.0
LY 303511 Hs Inhibitor Inhibition 65.4 101.0 95.0
MK2a inhibitor Hs Inhibitor Inhibition 69.9 106.0 92.0
LY 294002 Hs Inhibitor Inhibition 70.3 102.0 97.0
MEK inhibitor I Hs Inhibitor Inhibition 71.1 108.0 98.0
MEK inhibitor II Hs Inhibitor Inhibition 73.6 110.0 102.0
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 76.2 49.0 3.0
p38 MAP kinase inhibitor Hs Inhibitor Inhibition 77.3 122.0 104.0
PD 174265 Hs Inhibitor Inhibition 77.7 93.0 94.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
In endothelial cells of the vasculature, and in activated human mast cells, ERK serves as an anti-inflammatory signal that suppresses production of pro-inflammatory mediators [9,11]. In contrast, in astrocytes ERK2 plays a role in augmenting inflammation and gliosis in a demyelinating mouse model [15].
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 2 GO processes
GO:0038096 Fc-gamma receptor signaling pathway involved in phagocytosis TAS
GO:0043312 neutrophil degranulation TAS
Immuno Process:  Antigen presentation
GO Annotations:  Associated to 1 GO processes
GO:0072584 caveolin-mediated endocytosis TAS
Immuno Process:  Immune regulation
GO Annotations:  Associated to 4 GO processes
GO:0038095 Fc-epsilon receptor signaling pathway TAS
GO:0038096 Fc-gamma receptor signaling pathway involved in phagocytosis TAS
click arrow to show/hide IEA associations
GO:0050852 T cell receptor signaling pathway IEA
GO:0050853 B cell receptor signaling pathway IEA
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 5 GO processes
GO:0038095 Fc-epsilon receptor signaling pathway TAS
GO:0038096 Fc-gamma receptor signaling pathway involved in phagocytosis TAS
GO:0043312 neutrophil degranulation TAS
click arrow to show/hide IEA associations
GO:0050852 T cell receptor signaling pathway IEA
GO:0050853 B cell receptor signaling pathway IEA
Immuno Process:  Immune system development
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0048538 thymus development IEA
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 2 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0071356 cellular response to tumor necrosis factor IEA
GO:0097011 cellular response to granulocyte macrophage colony-stimulating factor stimulus IEA
Clinically-Relevant Mutations and Pathophysiology
Disease:  Chromosome 22q11.2 deletion syndrome, distal
Synonyms: Distal 22q11.2 microdeletion syndrome [Orphanet: ORPHA261330]
OMIM: 611867
Orphanet: ORPHA261330
References:  17
General Comments
The RAS/RAF/MEK (MAPK) signalling pathway is a major driver of malignancy, particularly in cancers induced by activating mutations in RAS and BRAF. Whilst BRAF and MEK inhibitors are already used clinically, in many cancers resistance to these inhibitors develops through reactivation of the pathway downstream of BRAF and MEK. As the terminal node in the MAPK signalling pathway ERK1 (MAPK3) and ERK2 (MAPK1) are not subject to the feedback reactivation mechanisms that can negate the effects of RAF or MEK blockade. ERK1/2 inhibitors offer potential clinical benefit for cancers in which existing drugs are ineffective. To our knowledge, no ERK1/2 inhibitors have yet progressed beyond Phase 1/2 clinical trial.

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. Aronov AM, Tang Q, Martinez-Botella G, Bemis GW, Cao J, Chen G, Ewing NP, Ford PJ, Germann UA, Green J et al.. (2009) Structure-guided design of potent and selective pyrimidylpyrrole inhibitors of extracellular signal-regulated kinase (ERK) using conformational control. J. Med. Chem., 52 (20): 6362-8. [PMID:19827834]

3. Blake JF, Burkard M, Chan J, Chen H, Chou K-J, Diaz D, Didley DA, Gaudino JJ, Gould SE, Grina J et al.. (2016) Discovery of ( S ) ‑ 1-(1-(4-Chloro-3- fl uorophenyl)-2-hydroxyethyl)-4-(2- ((1-methyl ‑ 1 H ‑ pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1 H ) ‑ one (GDC-0994), an Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Inhibitor in Early Clinical Development. Journal of Medicinal Chemistry, Online ahead of print.

4. Blake JF, Chicarelli MJ, Garrey RF, Gaudino J, Grina J, Moreno DA, Mohr PJ, Ren L, Schwarz J, Chen H et al.. (2013) Serine/threonine kinase inhibitors. Patent number: WO2013130976. Assignee: Array Biopharma Inc., Genentech, Inc.. Priority date: 01/03/2012. Publication date: 06/09/2013.

5. Chen F, Hancock CN, Macias AT, Joh J, Still K, Zhong S, MacKerell Jr AD, Shapiro P. (2006) Characterization of ATP-independent ERK inhibitors identified through in silico analysis of the active ERK2 structure. Bioorg. Med. Chem. Lett., 16 (24): 6281-7. [PMID:17000106]

6. 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]

7. 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]

8. Heightman TD, Berdini V, Braithwaite H, Buck IM, Cassidy M, Castro J, Courtin A, Day JEH, East C, Fazal L et al.. (2018) Fragment-Based Discovery of a Potent, Orally Bioavailable Inhibitor That Modulates the Phosphorylation and Catalytic Activity of ERK1/2. J. Med. Chem., 61 (11): 4978-4992. [PMID:29775310]

9. Kim HK. (2014) Role of ERK/MAPK signalling pathway in anti-inflammatory effects of Ecklonia cava in activated human mast cell line-1 cells. Asian Pacific Journal of Tropical Medicine, 7 (9): 703-708.

10. Li J, Malakhova M, Mottamal M, Reddy K, Kurinov I, Carper A, Langfald A, Oi N, Kim MO, Zhu F et al.. (2012) Norathyriol suppresses skin cancers induced by solar ultraviolet radiation by targeting ERK kinases. Cancer Res., 72 (1): 260-70. [PMID:22084399]

11. Maeng YS, Min JK, Kim JH, Yamagishi A, Mochizuki N, Kwon JY, Park YW, Kim YM, Kwon YG. (2006) ERK is an anti-inflammatory signal that suppresses expression of NF-kappaB-dependent inflammatory genes by inhibiting IKK activity in endothelial cells. Cell. Signal., 18 (7): 994-1005. [PMID:16242916]

12. Morris EJ, Jha S, Restaino CR, Dayananth P, Zhu H, Cooper A, Carr D, Deng Y, Jin W, Black S et al.. (2013) Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors. Cancer Discov, 3 (7): 742-50. [PMID:23614898]

13. Moschos SJ, Sullivan RJ, Hwu WJ, Ramanathan RK, Adjei AA, Fong PC, Shapira-Frommer R, Tawbi HA, Rubino J, Rush 3rd TS et al.. (2018) Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors. JCI Insight, 3 (4). [PMID:29467321]

14. Ohori M, Kinoshita T, Okubo M, Sato K, Yamazaki A, Arakawa H, Nishimura S, Inamura N, Nakajima H, Neya M et al.. (2005) Identification of a selective ERK inhibitor and structural determination of the inhibitor-ERK2 complex. Biochem. Biophys. Res. Commun., 336 (1): 357-63. [PMID:16139248]

15. Okazaki R, Doi T, Hayakawa K, Morioka K, Imamura O, Takishima K, Hamanoue M, Sawada Y, Nagao M, Tanaka S et al.. (2016) The crucial role of Erk2 in demyelinating inflammation in the central nervous system. J Neuroinflammation, 13 (1): 235. [PMID:27596241]

16. Ring DB, Johnson KW, Henriksen EJ, Nuss JM, Goff D, Kinnick TR, Ma ST, Reeder JW, Samuels I, Slabiak T et al.. (2003) Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo. Diabetes, 52 (3): 588-95. [PMID:12606497]

17. Verhoeven W, Egger J, Brunner H, de Leeuw N. (2011) A patient with a de novo distal 22q11.2 microdeletion and anxiety disorder. Am. J. Med. Genet. A, 155A (2): 392-7. [PMID:21271660]

18. Ward RA, Colclough N, Challinor M, Debreczeni JE, Eckersley K, Fairley G, Feron L, Flemington V, Graham MA, Greenwood R et al.. (2015) Structure-Guided Design of Highly Selective and Potent Covalent Inhibitors of ERK1/2. J. Med. Chem., 58 (11): 4790-801. [PMID:25977981]

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

ERK subfamily: mitogen-activated protein kinase 1. Last modified on 01/06/2018. Accessed on 25/05/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=1495.