| Target General Infomation |
| Target ID |
T35940
|
| Former ID |
TTDR00148
|
| Target Name |
Dual specificity mitogen-activated protein kinase kinase 1
|
| Gene Name |
MAP2K1
|
| Synonyms |
ERK activator kinase 1; MAP kinase kinase 1; MAPK/ERKkinase 1; MAPKK 1; MEK1; Mitogen-activated protein kinase kinase 1; MAP2K1
|
| Target Type |
Discontinued
|
| Disease |
Cancer [ICD9: 140-229; ICD10: C00-C96] |
|---|
| Function |
Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Binding of extracellular ligands such as growth factors, cytokines and hormones to their cell-surface receptors activates RAS and this initiates RAF1 activation. RAF1 then further activates the dual-specificity protein kinases MAP2K1/MEK1 and MAP2K2/MEK2. Both MAP2K1/MEK1 and MAP2K2/MEK2 function specifically in the MAPK/ERK cascade, and catalyze the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in the extracellular signal-regulated kinases MAPK3/ERK1 and MAPK1/ERK2, leading to their activation and further transduction of the signal within the MAPK/ERK cascade. Depending on the cellular context, this pathway mediates diverse biological functions such as cell growth, adhesion, survival and differentiation, predominantly through the regulation of transcription, metabolism and cytoskeletal rearrangements. One target of the MAPK/ERK cascade is peroxisome proliferator- activated receptor gamma (PPARG), a nuclear receptor that promotes differentiation and apoptosis. MAP2K1/MEK1 has been shown to export PPARG from the nucleus. The MAPK/ERK cascade is also involved in the regulation of endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC), as well as in the fragmentation of the Golgi apparatus during mitosis.
|
| BioChemical Class |
Kinase
|
| Target Validation |
T35940
|
| UniProt ID |
|
| EC Number |
EC 2.7.12.2
|
| Sequence |
MPKKKPTPIQLNPAPDGSAVNGTSSAETNLEALQKKLEELELDEQQRKRLEAFLTQKQKV
GELKDDDFEKISELGAGNGGVVFKVSHKPSGLVMARKLIHLEIKPAIRNQIIRELQVLHE
CNSPYIVGFYGAFYSDGEISICMEHMDGGSLDQVLKKAGRIPEQILGKVSIAVIKGLTYL
REKHKIMHRDVKPSNILVNSRGEIKLCDFGVSGQLIDSMANSFVGTRSYMSPERLQGTHY
SVQSDIWSMGLSLVEMAVGRYPIPPPDAKELELMFGCQVEGDAAETPPRPRTPGRPLSSY
GMDSRPPMAIFELLDYIVNEPPPKLPSGVFSLEFQDFVNKCLIKNPAERADLKQLMVHAF
IKRSDAEEVDFAGWLCSTIGLNQPSTPTHAAGV
|
| Drugs and Mode of Action |
| Drug(s) |
RDEA-436 |
Drug Info |
Discontinued in Phase 1 |
Cancer |
[1] |
|---|
| Inhibitor |
4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole |
Drug Info |
[2] |
|---|
| 4,5-Dibromo-1H-pyrrole-2-carboxylic acid amide |
Drug Info |
[3] |
| 5-phenylamino-4-cyano-3-hydroxy-isothiazole |
Drug Info |
[4] |
| ALDISIN |
Drug Info |
[3] |
| DEBROMOHYMENIALDISINE |
Drug Info |
[3] |
| OROIDIN |
Drug Info |
[3] |
| RDEA-436 |
Drug Info |
[5] |
| REVERSINE |
Drug Info |
[6] |
| Target Expression Profile (TEP) and Drug Resistance Mutation (DRM) |
| TEP |
EXP Info
|
| DRM |
DRM Info
|
| Pathways |
|
KEGG Pathway
|
MAPK signaling pathway
|
|
ErbB signaling pathway
|
|
Ras signaling pathway
|
|
Rap1 signaling pathway
|
|
cGMP-PKG signaling pathway
|
|
cAMP signaling pathway
|
|
Chemokine signaling pathway
|
|
HIF-1 signaling pathway
|
|
FoxO signaling pathway
|
|
Sphingolipid signaling pathway
|
|
Oocyte meiosis
|
|
PI3K-Akt signaling pathway
|
|
Vascular smooth muscle contraction
|
|
Dorso-ventral axis formation
|
|
VEGF signaling pathway
|
|
Osteoclast differentiation
|
|
Focal adhesion
|
|
Gap junction
|
|
Signaling pathways regulating pluripotency of stem cells
|
|
Toll-like receptor signaling pathway
|
|
Natural killer cell mediated cytotoxicity
|
|
T cell receptor signaling pathway
|
|
B cell receptor signaling pathway
|
|
Fc epsilon RI signaling pathway
|
|
Fc gamma R-mediated phagocytosis
|
|
TNF signaling pathway
|
|
Long-term potentiation
|
|
Neurotrophin signaling pathway
|
|
Cholinergic synapse
|
|
Serotonergic synapse
|
|
Long-term depression
|
|
Regulation of actin cytoskeleton
|
|
Insulin signaling pathway
|
|
GnRH signaling pathway
|
|
Progesterone-mediated oocyte maturation
|
|
Estrogen signaling pathway
|
|
Melanogenesis
|
|
Prolactin signaling pathway
|
|
Thyroid hormone signaling pathway
|
|
Oxytocin signaling pathway
|
|
Prion diseases
|
|
Alcoholism
|
|
Hepatitis B
|
|
Influenza A
|
|
Pathways in cancer
|
|
Proteoglycans in cancer
|
|
MicroRNAs in cancer
|
|
Colorectal cancer
|
|
Renal cell carcinoma
|
|
Pancreatic cancer
|
|
Endometrial cancer
|
|
Glioma
|
|
Prostate cancer
|
|
Thyroid cancer
|
|
Melanoma
|
|
Bladder cancer
|
|
Chronic myeloid leukemia
|
|
Acute myeloid leukemia
|
|
Non-small cell lung cancer
|
|
Central carbon metabolism in cancer
|
|
Choline metabolism in cancer
|
|
NetPath Pathway
|
FSH Signaling Pathway
|
|
TGF_beta_Receptor Signaling Pathway
|
|
PANTHER Pathway
|
Angiogenesis
|
|
B cell activation
|
|
EGF receptor signaling pathway
|
|
Endothelin signaling pathway
|
|
FGF signaling pathway
|
|
Insulin/IGF pathway-mitogen activated protein kinase kinase/MAP kinase cascade
|
|
Integrin signalling pathway
|
|
PDGF signaling pathway
|
|
T cell activation
|
|
Toll receptor signaling pathway
|
|
VEGF signaling pathway
|
|
Ras Pathway
|
|
Angiotensin II-stimulated signaling through G proteins and beta-arrestin
|
|
CCKR signaling map ST
|
|
Pathway Interaction Database
|
Fc-epsilon receptor I signaling in mast cells
|
|
Endothelins
|
|
BCR signaling pathway
|
|
GMCSF-mediated signaling events
|
|
Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met)
|
|
EPHB forward signaling
|
|
SHP2 signaling
|
|
Netrin-mediated signaling events
|
|
mTOR signaling pathway
|
|
Class IB PI3K non-lipid kinase events
|
|
IL2-mediated signaling events
|
|
Ras signaling in the CD4+ TCR pathway
|
|
Ceramide signaling pathway
|
|
IFN-gamma pathway
|
|
ErbB1 downstream signaling
|
|
ErbB2/ErbB3 signaling events
|
|
FOXM1 transcription factor network
|
|
PDGFR-beta signaling pathway
|
|
Neurotrophic factor-mediated Trk receptor signaling
|
|
Nongenotropic Androgen signaling
|
|
Hedgehog signaling events mediated by Gli proteins
|
|
CXCR3-mediated signaling events
|
|
Signaling events mediated by Stem cell factor receptor (c-Kit)
|
|
Signaling events mediated by VEGFR1 and VEGFR2
|
|
Cellular roles of Anthrax toxin
|
|
Trk receptor signaling mediated by the MAPK pathway
|
|
Downstream signaling in na&
|
|
#xef
|
|
ve CD8+ T cells
|
|
Signaling events mediated by focal adhesion kinase
|
|
PathWhiz Pathway
|
Fc Epsilon Receptor I Signaling in Mast Cells
|
|
Insulin Signalling
|
|
Reactome
|
MAPK3 (ERK1) activation
|
|
Uptake and function of anthrax toxins
|
|
RAF activation
|
|
MAP2K and MAPK activation
|
|
Negative feedback regulation of MAPK pathway
|
|
MAP3K8 (TPL2)-dependent MAPK1/3 activation
|
|
WikiPathways
|
Toll-like receptor signaling pathway
|
|
Serotonin Receptor 4/6/7 and NR3C Signaling
|
|
Serotonin Receptor 2 and ELK-SRF/GATA4 signaling
|
|
Serotonin HTR1 Group and FOS Pathway
|
|
Estrogen signaling pathway
|
|
TCR Signaling Pathway
|
|
ErbB Signaling Pathway
|
|
Hypothetical Network for Drug Addiction
|
|
Senescence and Autophagy in Cancer
|
|
EPO Receptor Signaling
|
|
Regulation of Actin Cytoskeleton
|
|
IL-2 Signaling Pathway
|
|
Insulin Signaling
|
|
EGF/EGFR Signaling Pathway
|
|
MAPK Cascade
|
|
MAPK Signaling Pathway
|
|
TGF beta Signaling Pathway
|
|
IL-6 signaling pathway
|
|
Signaling of Hepatocyte Growth Factor Receptor
|
|
Focal Adhesion
|
|
Kit receptor signaling pathway
|
|
IL-3 Signaling Pathway
|
|
Bladder Cancer
|
|
Cardiac Hypertrophic Response
|
|
MAP kinase activation in TLR cascade
|
|
RAF/MAP kinase cascade
|
|
Nanoparticle-mediated activation of receptor signaling
|
|
Structural Pathway of Interleukin 1 (IL-1)
|
|
Genes and (Common) Pathways Underlying Drug Addiction
|
|
Nifedipine Activity
|
|
Aryl Hydrocarbon Receptor
|
|
PDGF Pathway
|
|
BDNF signaling pathway
|
|
Integrated Pancreatic Cancer Pathway
|
|
Oncostatin M Signaling Pathway
|
|
Corticotropin-releasing hormone
|
|
Interleukin-11 Signaling Pathway
|
|
AGE/RAGE pathway
|
|
B Cell Receptor Signaling Pathway
|
|
Prostate Cancer
|
|
Signaling Pathways in Glioblastoma
|
|
TSLP Signaling Pathway
|
|
IL-9 Signaling Pathway
|
|
Endothelin Pathways
|
|
IL-7 Signaling Pathway
|
|
Leptin signaling pathway
|
|
TSH signaling pathway
|
|
RANKL/RANK Signaling Pathway
|
|
IL-1 signaling pathway
|
|
Signaling by FGFR
|
|
Integrin-mediated Cell Adhesion
|
|
L1CAM interactions
|
|
MicroRNAs in cardiomyocyte hypertrophy
|
|
Regulation of toll-like receptor signaling pathway
|
|
Osteopontin Signaling
|
|
IL-5 Signaling Pathway
|
| References |
| REF 1 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800028258) |
|---|
| REF 2 | J Med Chem. 2004 Dec 2;47(25):6239-47.Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole. |
|---|
| REF 3 | J Med Chem. 2002 Jan 17;45(2):529-32.Aldisine alkaloids from the Philippine sponge Stylissa massa are potent inhibitors of mitogen-activated protein kinase kinase-1 (MEK-1). |
|---|
| REF 4 | Bioorg Med Chem Lett. 2006 Aug 1;16(15):3975-80. Epub 2006 May 24.Discovery of 3-hydroxy-4-carboxyalkylamidino-5-arylamino-isothiazoles as potent MEK1 inhibitors. |
|---|
| REF 5 | Clinical pipeline report, company report or official report of MedKoo Biosciences. |
|---|
| REF 6 | Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10482-7. Epub 2007 Jun 12.Reversine increases the plasticity of lineage-committed mammalian cells. |
|---|
