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mitogen-activated protein kinase kinase 2

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Target id: 2063

Nomenclature: mitogen-activated protein kinase kinase 2

Abbreviated Name: MEK2

Family: STE7 family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 400 19p13.3 MAP2K2 mitogen-activated protein kinase kinase 2
Mouse - 401 10 39.72 cM Map2k2 mitogen-activated protein kinase kinase 2
Rat - 400 7q11 Map2k2 mitogen activated protein kinase kinase 2
Previous and Unofficial Names Click here for help
ERK activator kinase 2 | MAP kinase kinase 2 | MKK2 | PRKMK2 | dual specificity mitogen-activated protein kinase kinase 2
Database Links Click here for help
Alphafold P36507 (Hs), Q63932 (Mm), P36506 (Rn)
BRENDA 2.7.12.2
ChEMBL Target CHEMBL2964 (Hs)
DrugBank Target P36507 (Hs)
Ensembl Gene ENSG00000126934 (Hs), ENSMUSG00000035027 (Mm), ENSRNOG00000020005 (Rn)
Entrez Gene 5605 (Hs), 26396 (Mm), 58960 (Rn)
Human Protein Atlas ENSG00000126934 (Hs)
KEGG Enzyme 2.7.12.2
KEGG Gene hsa:5605 (Hs), mmu:26396 (Mm), rno:58960 (Rn)
OMIM 601263 (Hs)
Orphanet ORPHA123140 (Hs)
Pharos P36507 (Hs)
RefSeq Nucleotide NM_030662 (Hs), NM_023138 (Mm), NM_133283 (Rn)
RefSeq Protein NP_109587 (Hs), NP_075627 (Mm), NP_579817 (Rn)
UniProtKB P36507 (Hs), Q63932 (Mm), P36506 (Rn)
Wikipedia MAP2K2 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  X-ray structure of the human mitogen-activated protein kinase kinase 2 (MEK2)in a complex with ligand and MgATP
PDB Id:  1S9I
Resolution:  3.2Å
Species:  Human
References:  5
Enzyme Reaction Click here for help
EC Number: 2.7.12.2

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
trametinib Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.7 pIC50 12
⤷ pIC50 8.7 (IC50 1.8x10-9 M) [12]
BI-847325 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.4 pIC50 9
⤷ pIC50 8.4 (IC50 4x10-9 M) [9]
voruciclib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.1 pIC50 6
⤷ pIC50 7.1 (IC50 8.7x10-8 M) [6]
MEK1/2 inhibitor Small molecule or natural product Primary target of this compound Hs Inhibition 6.7 pIC50 3
⤷ pIC50 6.7 (IC50 2.2x10-7 M) [3]
MS432 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.2 pIC50 10
⤷ pIC50 6.2 (IC50 5.9x10-7 M) [10]
Description: Determined in an in vitro biochemical assay, using a kinase-dead ERK mutant as the substrate for hMEK2.
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
binimetinib Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Negative 7.9 pIC50 7
⤷ pIC50 7.9 (IC50 1.2x10-8 M) [7]
refametinib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Negative 7.3 pIC50 4
⤷ pIC50 7.3 (IC50 4.7x10-8 M) [4]
cobimetinib Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Negative 6.7 pIC50 8
⤷ pIC50 6.7 (IC50 1.99x10-7 M) [8]
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: 2,11
Key to terms and symbols Click column headers to sort
Target used in screen: MEK2
Ligand Sp. Type Action Value Parameter
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.4 pKd
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.0 pKd
foretinib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.9 pKd
neratinib Small molecule or natural product Approved drug Hs Inhibitor Inhibition 7.6 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.6 pKd
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 7.0 pKd
SU-14813 Small molecule or natural product Hs Inhibitor Inhibition 6.9 pKd
PP-242 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.7 pKd
dovitinib Small molecule or natural product Hs Inhibitor Inhibition 6.5 pKd
CI-1040 Small molecule or natural product Hs Inhibitor Inhibition 6.4 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
Key to terms and symbols Click column headers to sort
Target used in screen: nd/MEK2
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.4
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.4
K-252a Small molecule or natural product Hs Inhibitor Inhibition 16.2
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 25.4
SU11652 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 41.4
dovitinib Small molecule or natural product Hs Inhibitor Inhibition 43.0
PD98059 Small molecule or natural product Hs Inhibitor Inhibition 69.2
PD 169316 Small molecule or natural product Hs Inhibitor Inhibition 71.7
GSK-3beta inhibitor VIII Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 73.5
JNK inhibitor V Small molecule or natural product Hs Inhibitor Inhibition 76.2
Displaying the top 10 most potent ligands  View all ligands in screen »
Immuno Process Associations
Immuno Process:  Immune system development
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Cardiofaciocutaneous syndrome 4; CFC4
Synonyms: Cardiofaciocutaneous syndrome [Orphanet: ORPHA1340]
OMIM: 615280
Orphanet: ORPHA1340

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. 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]

3. Fedorov O, Marsden B, Pogacic V, Rellos P, Müller S, Bullock AN, Schwaller J, Sundström M, Knapp S. (2007) A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc Natl Acad Sci USA, 104 (51): 20523-8. [PMID:18077363]

4. Iverson C, Larson G, Lai C, Yeh LT, Dadson C, Weingarten P, Appleby T, Vo T, Maderna A, Vernier JM et al.. (2009) RDEA119/BAY 869766: a potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancer. Cancer Res, 69 (17): 6839-47. [PMID:19706763]

5. Ohren JF, Chen H, Pavlovsky A, Whitehead C, Zhang E, Kuffa P, Yan C, McConnell P, Spessard C, Banotai C et al.. (2004) Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat Struct Mol Biol, 11 (12): 1192-7. [PMID:15543157]

6. Paiva C, Godbersen JC, Soderquist RS, Rowland T, Kilmarx S, Spurgeon SE, Brown JR, Srinivasa SP, Danilov AV. (2015) Cyclin-Dependent Kinase Inhibitor P1446A Induces Apoptosis in a JNK/p38 MAPK-Dependent Manner in Chronic Lymphocytic Leukemia B-Cells. PLoS ONE, 10 (11): e0143685. [PMID:26606677]

7. Pheneger J, Wallace, E, Marlow, A Hurley B, Lyssikatos J, Bendele AM, Lee PA. (2006) Characterization of ARRY-438162, a Potent MEK Inhibitor in Combination with Methotrexate or Ibuprofen in In Vivo Models of Arthritis.[abstract]. American College of Rheumatology 2006 Annual Scientific Meeting,: Abstract 794.

8. Rice KD, Aay N, Anand NK, Blazey CM, Bowles OJ, Bussenius J, Costanzo S, Curtis JK, Defina SC, Dubenko L et al.. (2012) Novel Carboxamide-Based Allosteric MEK Inhibitors: Discovery and Optimization Efforts toward XL518 (GDC-0973). ACS Med Chem Lett, 3 (5): 416-21. [PMID:24900486]

9. Sini P, Gürtler U, Zahn SK, Baumann C, Rudolph D, Baumgartinger R, Strauss E, Haslinger C, Tontsch-Grunt U, Waizenegger IC et al.. (2016) Pharmacological Profile of BI 847325, an Orally Bioavailable, ATP-Competitive Inhibitor of MEK and Aurora Kinases. Mol Cancer Ther, 15 (10): 2388-2398. [PMID:27496137]

10. Wei J, Hu J, Wang L, Xie L, Jin MS, Chen X, Liu J, Jin J. (2019) Discovery of a First-in-Class Mitogen-Activated Protein Kinase Kinase 1/2 Degrader. J Med Chem, 62 (23): 10897-10911. DOI: 10.1021/acs.jmedchem.9b01528 [PMID:31730343]

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]

12. Yamaguchi T, Kakefuda R, Tajima N, Sowa Y, Sakai T. (2011) Antitumor activities of JTP-74057 (GSK1120212), a novel MEK1/2 inhibitor, on colorectal cancer cell lines in vitro and in vivo. Int J Oncol, 39 (1): 23-31. [PMID:21523318]

How to cite this page

STE7 family: mitogen-activated protein kinase kinase 2. Last modified on 08/05/2023. Accessed on 18/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2063.