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mitogen-activated protein kinase 1

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Target id: 1495

Nomenclature: mitogen-activated protein kinase 1

Abbreviated Name: ERK2

Family: ERK subfamily

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 360 22q11.22 MAPK1 mitogen-activated protein kinase 1
Mouse - 358 16 10.53 cM Mapk1 mitogen-activated protein kinase 1
Rat - 358 11q23 Mapk1 mitogen activated protein kinase 1
Previous and Unofficial Names Click here for help
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 Click here for help
Alphafold P28482 (Hs), P63085 (Mm), P63086 (Rn)
BRENDA 2.7.11.24
ChEMBL Target CHEMBL4040 (Hs), CHEMBL2207 (Mm), CHEMBL5233 (Rn)
DrugBank Target P28482 (Hs)
Ensembl Gene ENSG00000100030 (Hs), ENSMUSG00000063358 (Mm), ENSRNOG00000001849 (Rn)
Entrez Gene 5594 (Hs), 26413 (Mm), 116590 (Rn)
Human Protein Atlas ENSG00000100030 (Hs)
KEGG Enzyme 2.7.11.24
KEGG Gene hsa:5594 (Hs), mmu:26413 (Mm), rno:116590 (Rn)
OMIM 176948 (Hs)
Orphanet ORPHA159910 (Hs)
Pharos P28482 (Hs)
RefSeq Nucleotide NM_002745 (Hs), NM_011949 (Mm), NM_053842 (Rn)
RefSeq Protein NP_002736 (Hs), NP_036079 (Mm), NP_001033752 (Mm), NP_446294 (Rn)
SynPHARM 85248 (in complex with compound 27 [PMID: 29775310])
80614 (in complex with ERK inhibitor II)
83697 (in complex with GDC-0994)
81089 (in complex with SCH772984)
81090 (in complex with SCH772984)
83976 (in complex with VTX-11e)
UniProtKB P28482 (Hs), P63085 (Mm), P63086 (Rn)
Wikipedia MAPK1 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Complex of ERK2 with norathyriol
PDB Id:  3SA0
Resolution:  1.59Å
Species:  Human
References:  13
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:  18
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
ERK inhibitor III Small molecule or natural product Primary target of this compound Hs Binding 4.9 pKd 6
⤷ pKd 4.9 (Kd 1.3x10-5 M) [6]
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 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition >8.7 pKi 2
⤷ pKi >8.7 (Ki <2x10-9 M) [2]
ERK inhibitor II Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.8 pKi 18
⤷ pKi 6.8 (Ki 1.4x10-7 M) [18]
rineterkib Small molecule or natural product Hs Inhibition 10.6 pIC50 3
⤷ pIC50 10.6 (IC50 2.61x10-11 M) [3]
Description: Potency against activated ERK2, determined in a kinase assay measuring ERK2-catalysed phosphorylation of EGF receptor-derived substrate peptide ([Biotin]-AHA-K-R-E-L-V-E-P-L-T-P-S-G-E-A-P-N-Q-A-L-L-R-[NH2])
ulixertinib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition >9.5 pIC50 22
⤷ pIC50 >9.5 (IC50 <3x10-10 M) [22]
Description: Biochemical assay determination
tizaterkib Small molecule or natural product Ligand has a PDB structure Hs Inhibition 9.2 pIC50 8
⤷ pIC50 9.2 (IC50 6.6x10-10 M) [8]
Description: Inhibition in an ERK2 biochemical assay
SCH772984 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 8.4 – 9.0 pIC50 16
⤷ pIC50 9.0 (IC50 1x10-9 M) [16]
pIC50 8.4 (IC50 4x10-9 M) [16]
ASTX029 Small molecule or natural product Ligand has a PDB structure Hs Inhibition 8.6 pIC50 10
⤷ pIC50 8.6 (IC50 2.7x10-9 M) [10]
compound 27 [PMID: 29775310] Small molecule or natural product Ligand has a PDB structure Hs Inhibition 8.5 pIC50 11
⤷ pIC50 8.5 (IC50 3x10-9 M) [11]
ravoxertinib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.8 – 8.5 pIC50 4-5
⤷ pIC50 7.8 – 8.5 (IC50 1.55x10-8 – 3.1x10-9 M) [4-5]
MK-8353 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.1 pIC50 17
⤷ pIC50 8.1 (IC50 8.8x10-9 M) [17]
Description: Measuring inhibition of activated ERK2 in a IMAP kinase assay.
edaxeterkib Small molecule or natural product Hs Inhibition >7.3 pIC50 14
⤷ pIC50 >7.3 (IC50 <5x10-8 M) [14]
Description: Binned IC50 value from patent; determined using the proprietary Z'- LYTE kinase assay.
laduviglusib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition <5.0 pIC50 20
⤷ pIC50 <5.0 (IC50 >1x10-5 M) [20]
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: 7,23
Key to terms and symbols Click column headers to sort
Target used in screen: ERK2
Ligand Sp. Type Action Value Parameter
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.5 pKd
erlotinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition <5.5 pKd
A-674563 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition <5.5 pKd
GSK690693 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition <5.5 pKd
ruboxistaurin Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition <5.5 pKd
SB203580 Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition <5.5 pKd
gefitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition <5.5 pKd
masitinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition <5.5 pKd
linifanib Small molecule or natural product Hs Inhibitor Inhibition <5.5 pKd
crizotinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand 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: 1,9
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 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 28.8 4.0 -3.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 48.0 5.0 -3.0
LY 303511 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 65.4 101.0 95.0
MK2a inhibitor Small molecule or natural product Hs Inhibitor Inhibition 69.9 106.0 92.0
LY 294002 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 70.3 102.0 97.0
MEK inhibitor I Small molecule or natural product Hs Inhibitor Inhibition 71.1 108.0 98.0
MEK inhibitor II Small molecule or natural product Hs Inhibitor Inhibition 73.6 110.0 102.0
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 76.2 49.0 3.0
p38 MAP kinase inhibitor Small molecule or natural product Hs Inhibitor Inhibition 77.3 122.0 104.0
PD 174265 Small molecule or natural product Ligand has a PDB structure 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 [12,15]. In contrast, in astrocytes ERK2 plays a role in augmenting inflammation and gliosis in a demyelinating mouse model [19].
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  Antigen presentation
Immuno Process:  Immune regulation
Immuno Process:  Cellular signalling
Immuno Process:  Immune system development
Immuno Process:  Cytokine production & signalling
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Chromosome 22q11.2 deletion syndrome, distal
Synonyms: Distal 22q11.2 microdeletion syndrome [Orphanet: ORPHA261330]
OMIM: 611867
Orphanet: ORPHA261330
References:  21
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. Bagdanoff JT, Ding Y, Han W, Huang Z, Jiang Q, Jin JX, Kou X, Lee P, Lindvall M, Min Z et al.. (2015) Aminoheteroaryl benzamides as kinase inhibitors. Patent number: WO2015066188A1. Assignee: Novartis Ag. Priority date: 01/11/2013. Publication date: 07/05/2015.

4. Blake JF, Burkard M, Chan J, Chen H, Chou KJ, Diaz D, Dudley DA, Gaudino JJ, Gould SE, Grina J et al.. (2016) Discovery of (S)-1-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (GDC-0994), an Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Inhibitor in Early Clinical Development. J Med Chem, 59 (12): 5650-60. [PMID:27227380]

5. 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.

6. 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]

7. 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]

8. Flemington V, Davies EJ, Robinson D, Sandin LC, Delpuech O, Zhang P, Hanson L, Farrington P, Bell S, Falenta K et al.. (2021) AZD0364 Is a Potent and Selective ERK1/2 Inhibitor That Enhances Antitumor Activity in KRAS-Mutant Tumor Models when Combined with the MEK Inhibitor, Selumetinib. Mol Cancer Ther, 20 (2): 238-249. [PMID:33273059]

9. 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]

10. Heightman TD, Berdini V, Bevan L, Buck IM, Carr MG, Courtin A, Coyle JE, Day JEH, East C, Fazal L et al.. (2021) Discovery of ASTX029, A Clinical Candidate Which Modulates the Phosphorylation and Catalytic Activity of ERK1/2. J Med Chem, 64 (16): 12286-12303. [PMID:34387469]

11. 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]

12. 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. DOI: 10.1016/S1995-7645(14)60120-6

13. 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]

14. Li L, Wu T, Feng J, Ren P, Liu Y. (2015) Inhibitors of erk and methods of use. Patent number: WO2015051341A1. Assignee: Araxes Pharma Llc. Priority date: 03/10/2013. Publication date: 09/04/2015.

15. 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]

16. 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]

17. 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]

18. 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]

19. 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]

20. 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]

21. 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]

22. 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]

23. 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 28/09/2021. Accessed on 19/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=1495.