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mitogen-activated protein kinase kinase 1

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Target not currently curated in GtoImmuPdb

Target id: 2062

Nomenclature: mitogen-activated protein kinase kinase 1

Abbreviated Name: MEK1

Family: STE7 family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 393 15q22.31 MAP2K1 mitogen-activated protein kinase kinase 1
Mouse - 393 9 34.55 cM Map2k1 mitogen-activated protein kinase kinase 1
Rat - 393 8q24 Map2k1 mitogen activated protein kinase kinase 1
Previous and Unofficial Names Click here for help
dual specificity mitogen-activated protein kinase kinase 1 | ERK activator kinase 1 | MAP kinase kinase 1 | MAPKK1 | MKK1 | PRKMK1
Database Links Click here for help
Alphafold Q02750 (Hs), P31938 (Mm), Q01986 (Rn)
BRENDA 2.7.12.2
ChEMBL Target CHEMBL3587 (Hs), CHEMBL5860 (Mm)
DrugBank Target Q02750 (Hs)
Ensembl Gene ENSG00000169032 (Hs), ENSMUSG00000004936 (Mm), ENSRNOG00000010176 (Rn)
Entrez Gene 5604 (Hs), 26395 (Mm), 170851 (Rn)
Human Protein Atlas ENSG00000169032 (Hs)
KEGG Enzyme 2.7.12.2
KEGG Gene hsa:5604 (Hs), mmu:26395 (Mm), rno:170851 (Rn)
OMIM 176872 (Hs)
Orphanet ORPHA123135 (Hs)
Pharos Q02750 (Hs)
RefSeq Nucleotide NM_002755 (Hs), NM_008927 (Mm), NM_031643 (Rn)
RefSeq Protein NP_002746 (Hs), NP_032953 (Mm), NP_113831 (Rn)
SynPHARM 85068 (in complex with CH4987655)
83118 (in complex with cobimetinib)
80833 (in complex with PD 0325901)
80845 (in complex with refametinib)
80157 (in complex with selumetinib)
85069 (in complex with TAK-733)
UniProtKB Q02750 (Hs), P31938 (Mm), Q01986 (Rn)
Wikipedia MAP2K1 (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 1 (MEK1) in a ternary complex with compound 1, ATP-GS AND MG2P
PDB Id:  3EQC
Resolution:  1.8Å
Species:  Human
References:  7
Image of receptor 3D structure from RCSB PDB
Description:  X-ray structure of the human mitogen-activated protein kinase kinase 1 (MEK1) complexed with a potent inhibitor RDEA119 and MgATP
PDB Id:  3E8N
Ligand:  refametinib
Resolution:  2.5Å
Species:  Human
References:  15
Image of receptor 3D structure from RCSB PDB
Description:  Mitogen-activated protein kinase kinase 1 (MEK1) in complex with CH4987655 and MgAMP-PNP.
PDB Id:  3ORN
Ligand:  CH4987655
Resolution:  2.8Å
Species:  Human
References:  14
Image of receptor 3D structure from RCSB PDB
Description:  Crystal Structure of the Human Mitogen-activated protein kinase kinase 1 (MEK 1) in complex with ligand and MgATP.
PDB Id:  3PP1
Ligand:  TAK-733
Resolution:  2.7Å
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
GDC-0623 Small molecule or natural product Ligand has a PDB structure Hs Inhibition ~9.0 pKi 12
⤷ pKi ~9.0 (Ki ~1x10-9 M) [12]
Description: Measured in a fluorescence anisotropy assay using recombinant MEK1. Ki approximated from the graph in supplementary figure 1b.
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 9.0 – 9.1 pIC50 9,26
⤷ pIC50 9.0 – 9.1 (IC50 9.2x10-10 – 7x10-10 M) [9,26]
Description: Inhibition of unphosphorylated MEK1.
MAP855 Small molecule or natural product Hs Inhibition 8.3 pIC50 18
⤷ pIC50 8.3 (IC50 5x10-9 M) [18]
Description: Inhibition of the MAP kinase pathway determined as inhibition of ERK phosphorylation in a TR-FRET assay
E6201 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.3 pIC50 10
⤷ pIC50 8.3 (IC50 5.2x10-9 M) [10]
CH4987655 Small molecule or natural product Ligand has a PDB structure Hs Inhibition 8.3 pIC50 14
⤷ pIC50 8.3 (IC50 5.2x10-9 M) [14]
zapnometinib Small molecule or natural product Hs Inhibition 8.2 pIC50 21
⤷ pIC50 8.2 (IC50 5.73x10-9 M) [21]
mirdametinib Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 8.1 pIC50 11
⤷ pIC50 8.1 (IC50 7x10-9 M) [11]
MEK inhibitor I Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.9 pIC50 24
⤷ pIC50 7.9 (IC50 1.2x10-8 M) [24]
BI-847325 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.6 pIC50 20
⤷ pIC50 7.6 (IC50 2.5x10-8 M) [20]
avutometinib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.8 pIC50 2
⤷ pIC50 6.8 (IC50 1.6x10-7 M) [2]
nedometinib Small molecule or natural product Hs Inhibition 6.6 pIC50 16
⤷ pIC50 6.6 (IC50 2.46x10-7 M) [16]
MEK inhibitor II Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.4 pIC50 6
⤷ pIC50 6.4 (IC50 3.8x10-7 M) [6]
MS432 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.8 pIC50 23
⤷ pIC50 5.8 (IC50 1.5x10-6 M) [23]
Description: Determined in an in vitro biochemical assay, using a kinase-dead ERK mutant as the substrate for hMEK1.
Inhibitor Comments
Trametinib inhibits both MAP2K1 (MEK1) and MAP2K2 (MEK2).
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
CI-1040 Small molecule or natural product Primary target of this compound Hs Negative 6.9 pKd 4
⤷ pKd 6.9 (Kd 1.2x10-7 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 9.1 pIC50 19
⤷ pIC50 9.1 (IC50 9x10-10 M) [19]
Description: Biochemical assay measuring MEK-induced phosphorylation of ERK residues T202 and Y204.
TAK-733 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 8.5 pIC50 5
⤷ pIC50 8.5 (IC50 3.2x10-9 M) [5]
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 17
⤷ pIC50 7.9 (IC50 1.2x10-8 M) [17]
selumetinib Small molecule or natural product Approved drug Primary target of this compound Ligand has a PDB structure Hs Negative 7.8 – 7.9 pIC50 13,27
⤷ pIC50 7.8 – 7.9 (IC50 1.41x10-8 – 1.2x10-8 M) [13,27]
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 7.7 pIC50 15
⤷ pIC50 7.7 (IC50 1.9x10-8 M) [15]
compound 3 [PMID: 31804822] Small molecule or natural product Hs Negative 7.0 pIC50 22
⤷ pIC50 7.0 (IC50 1x10-7 M) [22]
CI-1040 Small molecule or natural product Oc Negative 6.5 pIC50 3
⤷ pIC50 6.5 (IC50 3x10-7 M) [3]
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: 4,25
Key to terms and symbols Click column headers to sort
Target used in screen: MEK1
Ligand Sp. Type Action Value Parameter
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.5 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 7.8 pKd
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.7 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.7 pKd
PP-242 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.3 pKd
SU-14813 Small molecule or natural product Hs Inhibitor Inhibition 7.1 pKd
selumetinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 7.0 pKd
CI-1040 Small molecule or natural product Hs Inhibitor Inhibition 6.9 pKd
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.9 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: 1,8
Key to terms and symbols Click column headers to sort
Target used in screen: MEK1/MEK1
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 3.8 3.0 0.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 23.6 0.0 0.0
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 29.5 40.0 51.0
SU11652 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 33.1 21.0 8.0
Syk inhibitor Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 63.6 42.0 19.0
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 65.3
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 67.8
PD98059 Small molecule or natural product Hs Inhibitor Inhibition 69.1 103.0 111.0
p38 MAP kinase inhibitor Small molecule or natural product Hs Inhibitor Inhibition 70.1 111.0 102.0
PD 169316 Small molecule or natural product Hs Inhibitor Inhibition 74.3 109.0 127.0
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 3; CFC3
Synonyms: Cardiofaciocutaneous syndrome [Orphanet: ORPHA1340]
OMIM: 615279
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. Aoki T, Hyohdoh I, Furuichi N, Ozawa S, Watanabe F, Matsushita M, Sakaitani M, Morikami K, Takanashi K, Harada N et al.. (2014) Optimizing the Physicochemical Properties of Raf/MEK Inhibitors by Nitrogen Scanning. ACS Med Chem Lett, 5 (4): 309-14. [PMID:24900832]

3. Davies SP, Reddy H, Caivano M, Cohen P. (2000) Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J, 351 (Pt 1): 95-105. [PMID:10998351]

4. 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]

5. Dong Q, Dougan DR, Gong X, Halkowycz P, Jin B, Kanouni T, O'Connell SM, Scorah N, Shi L, Wallace MB et al.. (2011) Discovery of TAK-733, a potent and selective MEK allosteric site inhibitor for the treatment of cancer. Bioorg Med Chem Lett, 21 (5): 1315-9. [PMID:21310613]

6. 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]

7. Fischmann TO, Smith CK, Mayhood TW, Myers JE, Reichert P, Mannarino A, Carr D, Zhu H, Wong J, Yang RS et al.. (2009) Crystal structures of MEK1 binary and ternary complexes with nucleotides and inhibitors. Biochemistry, 48 (12): 2661-74. [PMID:19161339]

8. 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]

9. Gilmartin AG, Bleam MR, Groy A, Moss KG, Minthorn EA, Kulkarni SG, Rominger CM, Erskine S, Fisher KE, Yang J et al.. (2011) GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition. Clin Cancer Res, 17 (5): 989-1000. [PMID:21245089]

10. Goto M, Chow J, Muramoto K, Chiba K, Yamamoto S, Fujita M, Obaishi H, Tai K, Mizui Y, Tanaka I et al.. (2009) E6201 [(3S,4R,5Z,8S,9S,11E)-14-(ethylamino)-8, 9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione], a novel kinase inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)-1 and MEK kinase-1: in vitro characterization of its anti-inflammatory and antihyperproliferative activities. J Pharmacol Exp Ther, 331 (2): 485-95. [PMID:19684251]

11. Hartung IV, Hitchcock M, Pühler F, Neuhaus R, Scholz A, Hammer S, Petersen K, Siemeister G, Brittain D, Hillig RC. (2013) Optimization of allosteric MEK inhibitors. Part 1: Venturing into underexplored SAR territories. Bioorg Med Chem Lett, 23 (8): 2384-90. [PMID:23474388]

12. Hatzivassiliou G, Haling JR, Chen H, Song K, Price S, Heald R, Hewitt JF, Zak M, Peck A, Orr C et al.. (2013) Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers. Nature, 501 (7466): 232-6. [PMID:23934108]

13. Huynh H, Soo KC, Chow PK, Tran E. (2007) Targeted inhibition of the extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) in the treatment of hepatocellular carcinoma. Mol Cancer Ther, 6 (1): 138-46. [PMID:17237274]

14. Isshiki Y, Kohchi Y, Iikura H, Matsubara Y, Asoh K, Murata T, Kohchi M, Mizuguchi E, Tsujii S, Hattori K et al.. (2011) Design and synthesis of novel allosteric MEK inhibitor CH4987655 as an orally available anticancer agent. Bioorg Med Chem Lett, 21 (6): 1795-801. [PMID:21316218]

15. 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]

16. Kincaid J, Duncton M. (2021) Pyrrolopyridine-aniline compounds for treatment of dermal disorders. Patent number: US11161845B2. Assignee: Nflection Therapeutics Inc. Priority date: 18/05/2018. Publication date: 02/11/2021.

17. 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.

18. Poddutoori R, Aardalen K, Aithal K, Barahagar SS, Belliappa C, Bock M, Chelur S, Gerken A, Gopinath S, Gruenenfelder B et al.. (2022) Discovery of MAP855, an Efficacious and Selective MEK1/2 Inhibitor with an ATP-Competitive Mode of Action. J Med Chem, 65 (5): 4350-4366. [PMID:35195996]

19. 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]

20. 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]

21. Tecle H, Shao J, Li Y, Kothe M, Kazmirski S, Penzotti J, Ding YH, Ohren J, Moshinsky D, Coli R et al.. (2009) Beyond the MEK-pocket: can current MEK kinase inhibitors be utilized to synthesize novel type III NCKIs? Does the MEK-pocket exist in kinases other than MEK?. Bioorg Med Chem Lett, 19 (1): 226-9. [PMID:19019675]

22. Vollmer S, Cunoosamy D, Lv H, Feng H, Li X, Nan Z, Yang W, Perry MWD. (2020) Design, Synthesis, and Biological Evaluation of MEK PROTACs. J Med Chem, 63 (1): 157-162. DOI: 10.1021/acs.jmedchem.9b00810 [PMID:31804822]

23. 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]

24. Wityak J, Hobbs FW, Gardner DS, Santella 3rd JB, Petraitis JJ, Sun JH, Favata MF, Daulerio AJ, Horiuchi KY, Copeland RA et al.. (2004) Beyond U0126. Dianion chemistry leading to the rapid synthesis of a series of potent MEK inhibitors. Bioorg Med Chem Lett, 14 (6): 1483-6. [PMID:15006386]

25. 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]

26. 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]

27. Yeh TC, Marsh V, Bernat BA, Ballard J, Colwell H, Evans RJ, Parry J, Smith D, Brandhuber BJ, Gross S et al.. (2007) Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clin Cancer Res, 13 (5): 1576-83. [PMID:17332304]

How to cite this page

STE7 family: mitogen-activated protein kinase kinase 1. Last modified on 11/08/2023. Accessed on 16/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2062.