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Target id: 1495
Nomenclature: mitogen-activated protein kinase 1
Abbreviated Name: ERK2
Family: ERK subfamily
Gene and Protein Information | ||||||
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 |
Database Links | |
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 | |||||||||||||
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Enzyme Reaction | ||||
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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 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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: 7,23 |
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Target used in screen: ERK2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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: 1,9 |
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Target used in screen: MAPK2/ERK2(MAPK1) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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]. |
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Clinically-Relevant Mutations and Pathophysiology | ||||||||||||||
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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. |
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]
ERK subfamily: mitogen-activated protein kinase 1. Last modified on 28/09/2021. Accessed on 04/12/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=1495.