Top ▲

mitogen-activated protein kinase 3

Click here for help

Target not currently curated in GtoImmuPdb

Target id: 1494

Nomenclature: mitogen-activated protein kinase 3

Abbreviated Name: ERK1

Family: ERK subfamily

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 379 16p11.2 MAPK3 mitogen-activated protein kinase 3
Mouse - 380 7 69.25 cM Mapk3 mitogen-activated protein kinase 3
Rat - 380 1q36 Mapk3 mitogen activated protein kinase 3
Previous and Unofficial Names Click here for help
ERT2 | Insulin-stimulated MAP2 kinase | extracellular signal-regulated kinase 1 | MAP kinase 1 | MAP kinase 3 | MAP kinase isoform p44 | MAPK 1 | MAPK 3 | microtubule-associated protein 2 kinase | MNK1 | p44-ERK1 | p44 MAP kinase | Mtap2k | PRKM3
Database Links Click here for help
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 Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Structural dissection of human mitogen-activated kinase ERK1
PDB Id:  2ZOQ
Resolution:  2.39Å
Species:  Human
References:  7
Image of receptor 3D structure from RCSB PDB
Description:  High resolution crystal structure of mitogen-activated protein kinase-activated protein kinase 3 (MK3)-inhibitor complex
PDB Id:  3FHR
Resolution:  1.9Å
Species:  Human
References:  4
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 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 6.4 pKi 9
pKi 6.4 (Ki 4.1x10-7 M) [9]
ulixertinib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition >9.5 pIC50 10
pIC50 >9.5 (IC50 <3x10-10 M) [10]
Description: Biochemical assay determination
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 8.2 – 8.5 pIC50 2-3
pIC50 8.2 – 8.5 (IC50 6.1x10-9 – 3.3x10-9 M) [2-3]
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 7.6 pIC50 8
pIC50 7.6 (IC50 2.3x10-8 M) [8]
Description: Measuring inhibition of activated ERK1 in a IMAP kinase assay.
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: 5,11

Key to terms and symbols Click column headers to sort
Target used in screen: ERK1
Ligand Sp. Type Action Value Parameter
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.4 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 Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition <5.5 pKd
crizotinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition <5.5 pKd
linifanib Small molecule or natural product 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: 1,6

Key to terms and symbols Click column headers to sort
Target used in screen: MAPK1/ERK1
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 11.6 5.0 0.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 24.4 10.0 -1.0
ERK inhibitor II Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 65.8 21.0 3.0
p38 MAP kinase inhibitor III Small molecule or natural product Hs Inhibitor Inhibition 68.0 115.0 70.0
JAK3 inhibitor VI Small molecule or natural product Hs Inhibitor Inhibition 71.8 25.0 1.0
Gö 6976 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 72.6 52.0 51.0
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 78.9 29.0 3.0
fascaplysin Small molecule or natural product Hs Inhibitor Inhibition 79.7 85.0 94.0
GSK-3 inhibitor XIII Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 80.8 83.0 83.0
GSK-3 inhibitor IX Small molecule or natural product Hs Inhibitor Inhibition 83.3 102.0 80.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 2 GO processes
GO:0038096 Fc-gamma receptor signaling pathway involved in phagocytosis TAS
click arrow to show/hide IEA associations
GO:0010759 positive regulation of macrophage chemotaxis IEA
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 3 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:0010759 positive regulation of macrophage chemotaxis IEA
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 2 GO processes
GO:0070498 interleukin-1-mediated signaling pathway IMP
click arrow to show/hide IEA associations
GO:0071356 cellular response to tumor necrosis factor IEA
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 2 GO processes
GO:0038095 Fc-epsilon receptor signaling pathway TAS
GO:0038096 Fc-gamma receptor signaling pathway involved in phagocytosis TAS
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:  Chemotaxis & migration
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0010759 positive regulation of macrophage chemotaxis IEA
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

Show »

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. 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]

3. 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.

4. Cheng R, Felicetti B, Palan S, Toogood-Johnson I, Scheich C, Barker J, Whittaker M, Hesterkamp T. (2010) High-resolution crystal structure of human Mapkap kinase 3 in complex with a high affinity ligand. Protein Sci., 19 (1): 168-73. [PMID:19937655]

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. 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. Kinoshita T, Yoshida I, Nakae S, Okita K, Gouda M, Matsubara M, Yokota K, Ishiguro H, Tada T. (2008) Crystal structure of human mono-phosphorylated ERK1 at Tyr204. Biochem. Biophys. Res. Commun., 377 (4): 1123-7. [PMID:18983981]

8. 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]

9. 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]

10. 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]

11. 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 3. Last modified on 01/06/2018. Accessed on 02/12/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1494.