Target Information

Target General Infomation
Target ID
T23003
Former ID
TTDI01775
Target Name
MEK protein kinase
Target Type
Successful
Disease Breast cancer; Colon tumor; NSCLC [ICD10: C50]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Colorectal cancer [ICD9: 153, 154; ICD10: C18-C21]
Melanoma [ICD9: 172; ICD10: C43]
Non-small-cell lung cancer; Melanoma [ICD9: 162, 172; ICD10: C33-C34, C43]
Psoriasis [ICD9: 696; ICD10: L40]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
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, leadingto 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
EC Number
EC 2.7.12.2
Drugs and Mode of Action
Drug(s) Trametinib Drug Info Approved Melanoma [1], [2]
ARRY-162 Drug Info Phase 3 Melanoma [3]
BAY 86-9766 Drug Info Phase 3 Cancer [4], [5]
AZD6244 Drug Info Phase 2 Non-small-cell lung cancer; Melanoma [6], [7]
E6201 Drug Info Phase 2 Psoriasis [8], [9]
MSC1936369B Drug Info Phase 2 Colorectal cancer [10], [11]
PD-0325901 Drug Info Phase 2 Breast cancer; Colon tumor; NSCLC [12], [13]
WX-554 Drug Info Phase 1/2 Cancer [14]
ARRY-300 Drug Info Phase 1 Cancer [15]
BI-847325 Drug Info Phase 1 Solid tumours [16]
RG7304 Drug Info Phase 1 Solid tumours [17]
RG7420 Drug Info Phase 1 Solid tumours [18]
RO-5126766 Drug Info Phase 1 Cancer [19]
TAK-733 Drug Info Phase 1 Solid tumours [20]
AZD8330 Drug Info Discontinued in Phase 1 Solid tumours [21], [22]
RG-7167 Drug Info Discontinued in Phase 1 Solid tumours [23]
RO-4987655 Drug Info Discontinued in Phase 1 Cancer [23]
Modulator ARRY-162 Drug Info [24]
ARRY-300 Drug Info [25]
AZD6244 Drug Info
AZD8330 Drug Info [24]
BAY 86-9766 Drug Info
BI-847325 Drug Info
E6201 Drug Info [26]
MSC1936369B Drug Info [10]
PD-0325901 Drug Info [24]
RG7420 Drug Info [24]
RO-4987655 Drug Info [24]
RO-5126766 Drug Info
TAK-733 Drug Info [24]
Trametinib Drug Info [1]
WX-554 Drug Info [24]
Inhibitor CIP-137401 Drug Info [27]
G-573 Drug Info [27]
MEK inhibitor I Drug Info [28]
NSC-686549 Drug Info [29]
RG-7167 Drug Info [27]
RG7304 Drug Info [30]
RO-4920506 Drug Info [27]
SL-327 Drug Info [29]
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
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
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
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
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
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 12013 FDA drug approvals. Nat Rev Drug Discov. 2014 Feb;13(2):85-9.
REF 2(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6495).
REF 3Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800024415)
REF 4Allosteric MEK1/2 inhibitor refametinib (BAY 86-9766) in combination with sorafenib exhibits antitumor activity in preclinical murine and rat models of hepatocellular carcinoma. Neoplasia. 2013 Oct;15(10):1161-71.
REF 5(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7942).
REF 6Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.
REF 7(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5665).
REF 8ClinicalTrials.gov (NCT02418000) A Study of E6201 for the Treatment of Advanced Hematologic Malignancies With FLT3 Mutation. U.S. National Institutes of Health.
REF 9(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7836).
REF 10Antitumor activity of pimasertib, a selective MEK 1/2 inhibitor, in combination with PI3K/mTOR inhibitors or with multi-targeted kinase inhibitors in pimasertib-resistant human lung and colorectal cancer cells. Int J Cancer. 2013 Nov;133(9):2089-101.
REF 11(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7872).
REF 12(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7935).
REF 13Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800020671)
REF 14ClinicalTrials.gov (NCT01581060) Phase I/II Dose-escalation Study to Investigate Safety and Pharmacokinetics/ Pharmacodynamics of WX-554 in Patients With Solid Tumours. U.S. National Institutes of Health.
REF 15ClinicalTrials.gov (NCT00828165) A Safety Study of ARRY-300 in Healthy Subjects. U.S. National Institutes of Health.
REF 16ClinicalTrials.gov (NCT01324830) Monotherapy Dose Finding With BI 847325 in Solid Tumours. U.S. National Institutes of Health.
REF 17Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800029782)
REF 18ClinicalTrials.gov (NCT01106599) A Study Evaluating the Safety, Tolerability, and Pharmacokinetics of GDC-0623 in Patients With Locally Advanced or Metastatic Solid Tumors. U.S. National Institutes of Health.
REF 19ClinicalTrials.gov (NCT02407509) Phase I Trial of RO5126766. U.S. National Institutes of Health.
REF 20ClinicalTrials.gov (NCT00948467) Study of TAK-733 in Adult Patients With Advanced Nonhematologic Malignancies. U.S. National Institutes of Health.
REF 21(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 8474).
REF 22Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026144)
REF 23Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800028214)
REF 24MEK and the inhibitors: from bench to bedside. J Hematol Oncol. 2013; 6: 27.
REF 25MEK and the inhibitors: from bench to bedside. J Hematol Oncol. 2013 Apr 12;6:27.
REF 26E6201, a novel kinase inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-1 and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase-1: in vivo effects on cutaneous inflammatory responses by topical administration. J Pharmacol Exp Ther. 2010 Oct;335(1):23-31.
REF 27(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2063).
REF 28Beyond U0126. Dianion chemistry leading to the rapid synthesis of a series of potent MEK inhibitors. Bioorg Med Chem Lett. 2004 Mar 22;14(6):1483-6.
REF 29Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20523-8. Epub 2007 Dec 11.A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases.
REF 30Clinical pipeline report, company report or official report of Roche.

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