mitogen-activated protein kinase kinase 1 | STE7 family | IUPHAR/BPS Guide to PHARMACOLOGY

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mitogen-activated protein kinase kinase 1

Target not currently curated in GtoImmuPdb

Target id: 2062

Nomenclature: mitogen-activated protein kinase kinase 1

Abbreviated Name: MEK1

Family: STE7 family

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 393 15q22.1-q22.33 MAP2K1 mitogen-activated protein kinase kinase 1
Mouse - 393 9 C Map2k1 mitogen-activated protein kinase kinase 1
Rat - 393 8 q24 Map2k1 mitogen activated protein kinase kinase 1
Previous and Unofficial Names
dual specificity mitogen-activated protein kinase kinase 1 | ERK activator kinase 1 | MAP kinase kinase 1 | MAPKK1 | MKK1 | PRKMK1
Database Links
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
RefSeq Nucleotide
RefSeq Protein
Selected 3D Structures
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
Resolution:  1.8Å
Species:  Human
References:  6
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:  14
Image of receptor 3D structure from RCSB PDB
Description:  Mitogen-activated protein kinase kinase 1 (MEK1) in complex with CH4987655 and MgAMP-PNP.
Ligand:  CH4987655
Resolution:  2.8Å
Species:  Human
References:  13
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:  4
Enzyme Reaction
EC Number:

Download all structure-activity data for this target as a CSV file

Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
GDC-0623 Hs Inhibition ~9.0 pKi 11
pKi ~9.0 (Ki ~1x10-9 M) [11]
Description: Measured in a fluorescence anisotropy assay using recombinant MEK1. Ki approximated from the graph in supplementary figure 1b.
trametinib Hs Inhibition 9.0 – 9.1 pIC50 8,21
pIC50 9.0 – 9.1 (IC50 9.2x10-10 – 7x10-10 M) [8,21]
Description: Inhibition of unphosphorylated MEK1.
E6201 Hs Inhibition 8.3 pIC50 9
pIC50 8.3 (IC50 5.2x10-9 M) [9]
CH4987655 Hs Inhibition 8.3 pIC50 13
pIC50 8.3 (IC50 5.2x10-9 M) [13]
PD 0325901 Hs Inhibition 8.1 pIC50 10
pIC50 8.1 (IC50 7x10-9 M) [10]
MEK inhibitor I Hs Inhibition 7.9 pIC50 19
pIC50 7.9 (IC50 1.2x10-8 M) [19]
MEK inhibitor II Hs Inhibition 6.4 pIC50 5
pIC50 6.4 (IC50 3.8x10-7 M) [5]
MS432 Hs Inhibition 5.8 pIC50 18
pIC50 5.8 (IC50 1.5x10-6 M) [18]
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 Hs Negative 6.9 pKd 3
pKd 6.9 (Kd 1.2x10-7 M) [3]
cobimetinib Hs Negative 9.1 pIC50 16
pIC50 9.1 (IC50 9x10-10 M) [16]
Description: Biochemical assay measuring MEK-induced phosphorylation of ERK residues T202 and Y204.
TAK-733 Hs Inhibition 8.5 pIC50 4
pIC50 8.5 (IC50 3.2x10-9 M) [4]
binimetinib Hs Negative 7.9 pIC50 15
pIC50 7.9 (IC50 1.2x10-8 M) [15]
selumetinib Hs Negative 7.8 – 7.9 pIC50 12,22
pIC50 7.8 – 7.9 (IC50 1.41x10-8 – 1.2x10-8 M) [12,22]
refametinib Hs Negative 7.7 pIC50 14
pIC50 7.7 (IC50 1.9x10-8 M) [14]
compound 3 [PMID: 31804822] Hs Negative 7.0 pIC50 17
pIC50 7.0 (IC50 1x10-7 M) [17]
CI-1040 Oc Negative 6.5 pIC50 2
pIC50 6.5 (IC50 3x10-7 M) [2]
DiscoveRx KINOMEscan® screen
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
Reference: 3,20

Key to terms and symbols Click column headers to sort
Target used in screen: MEK1
Ligand Sp. Type Action Value Parameter
lestaurtinib Hs Inhibitor Inhibition 8.5 pKd
foretinib Hs Inhibitor Inhibition 7.9 pKd
neratinib Hs Inhibitor Inhibition 7.8 pKd
bosutinib Hs Inhibitor Inhibition 7.7 pKd
staurosporine Hs Inhibitor Inhibition 7.7 pKd
PP-242 Hs Inhibitor Inhibition 7.3 pKd
SU-14813 Hs Inhibitor Inhibition 7.1 pKd
selumetinib Hs Inhibitor Inhibition 7.0 pKd
CI-1040 Hs Inhibitor Inhibition 6.9 pKd
sunitinib 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
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.

Reference: 1,7

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 Hs Inhibitor Inhibition 3.8 3.0 0.0
K-252a Hs Inhibitor Inhibition 23.6 0.0 0.0
SB 218078 Hs Inhibitor Inhibition 29.5 40.0 51.0
SU11652 Hs Inhibitor Inhibition 33.1 21.0 8.0
Syk inhibitor Hs Inhibitor Inhibition 63.6 42.0 19.0
bosutinib Hs Inhibitor Inhibition 65.3
sunitinib Hs Inhibitor Inhibition 67.8
PD98059 Hs Inhibitor Inhibition 69.1 103.0 111.0
p38 MAP kinase inhibitor Hs Inhibitor Inhibition 70.1 111.0 102.0
PD 169316 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
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0048538 thymus development IEA
Clinically-Relevant Mutations and Pathophysiology
Disease:  Cardiofaciocutaneous syndrome 3; CFC3
Synonyms: Cardiofaciocutaneous syndrome [Orphanet: ORPHA1340]
OMIM: 615279
Orphanet: ORPHA1340


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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. 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]

3. 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]

4. 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]

5. 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. U.S.A., 104 (51): 20523-8. [PMID:18077363]

6. 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]

7. 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]

8. 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]

9. 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]

10. 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]

11. 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]

12. 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]

13. 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]

14. 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]

15. 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.

16. 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]

17. 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]

18. 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]

19. 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]

20. 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]

21. 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]

22. 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 20/01/2020. Accessed on 25/09/2020. IUPHAR/BPS Guide to PHARMACOLOGY,