Target Information
Target General Infomation | |||||
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Target ID |
T23003
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Former ID |
TTDI01775
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Target Name |
MEK protein kinase
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Target Type |
Successful
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Disease | Breast cancer; Colon tumor; NSCLC [ICD10: C50] | ||||
Colorectal cancer [ICD9: 153, 154; ICD10: C18-C21] | |||||
Cancer [ICD9: 140-229; ICD10: C00-C96] | |||||
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.
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BioChemical Class |
Kinase
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EC Number |
EC 2.7.12.2
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Drugs and Mode of Action | |||||
Drug(s) | Trametinib | Drug Info | Approved | Melanoma | [532651], [541630] |
ARRY-162 | Drug Info | Phase 3 | Melanoma | [548308] | |
BAY 86-9766 | Drug Info | Phase 3 | Cancer | [532538], [542857] | |
AZD6244 | Drug Info | Phase 2 | Non-small-cell lung cancer; Melanoma | [537114], [541008] | |
E6201 | Drug Info | Phase 2 | Psoriasis | [525154], [542779] | |
MSC1936369B | Drug Info | Phase 2 | Colorectal cancer | [532332], [542798] | |
PD-0325901 | Drug Info | Phase 2 | Breast cancer; Colon tumor; NSCLC | [542850], [547954] | |
WX-554 | Drug Info | Phase 1/2 | Cancer | [523880] | |
ARRY-300 | Drug Info | Phase 1 | Cancer | [522557] | |
BI-847325 | Drug Info | Phase 1 | Solid tumours | [523412] | |
RG7304 | Drug Info | Phase 1 | Solid tumours | [548874] | |
RG7420 | Drug Info | Phase 1 | Solid tumours | [523011] | |
RO-5126766 | Drug Info | Phase 1 | Cancer | [525139] | |
TAK-733 | Drug Info | Phase 1 | Solid tumours | [522743] | |
AZD8330 | Drug Info | Discontinued in Phase 1 | Solid tumours | [543160], [548509] | |
RG-7167 | Drug Info | Discontinued in Phase 1 | Solid tumours | [548738] | |
RO-4987655 | Drug Info | Discontinued in Phase 1 | Cancer | [548738] | |
Modulator | ARRY-162 | Drug Info | [544302] | ||
ARRY-300 | Drug Info | [532311] | |||
AZD6244 | Drug Info | ||||
AZD8330 | Drug Info | [544302] | |||
BAY 86-9766 | Drug Info | ||||
BI-847325 | Drug Info | ||||
E6201 | Drug Info | [531034] | |||
MSC1936369B | Drug Info | [532332] | |||
PD-0325901 | Drug Info | [544302] | |||
RG7420 | Drug Info | [544302] | |||
RO-4987655 | Drug Info | [544302] | |||
RO-5126766 | Drug Info | ||||
TAK-733 | Drug Info | [544302] | |||
Trametinib | Drug Info | [532651] | |||
WX-554 | Drug Info | [544302] | |||
Inhibitor | CIP-137401 | Drug Info | [543550] | ||
G-573 | Drug Info | [543550] | |||
MEK inhibitor I | Drug Info | [526985] | |||
NSC-686549 | Drug Info | [529213] | |||
RG-7167 | Drug Info | [543550] | |||
RG7304 | Drug Info | [551608] | |||
RO-4920506 | Drug Info | [543550] | |||
SL-327 | Drug Info | [529213] | |||
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 522557 | ClinicalTrials.gov (NCT00828165) A Safety Study of ARRY-300 in Healthy Subjects. U.S. National Institutes of Health. | ||||
Ref 522743 | ClinicalTrials.gov (NCT00948467) Study of TAK-733 in Adult Patients With Advanced Nonhematologic Malignancies. U.S. National Institutes of Health. | ||||
Ref 523011 | ClinicalTrials.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 523412 | ClinicalTrials.gov (NCT01324830) Monotherapy Dose Finding With BI 847325 in Solid Tumours. U.S. National Institutes of Health. | ||||
Ref 523880 | ClinicalTrials.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 525139 | ClinicalTrials.gov (NCT02407509) Phase I Trial of RO5126766. U.S. National Institutes of Health. | ||||
Ref 525154 | ClinicalTrials.gov (NCT02418000) A Study of E6201 for the Treatment of Advanced Hematologic Malignancies With FLT3 Mutation. U.S. National Institutes of Health. | ||||
Ref 532332 | Antitumor 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 532538 | Allosteric 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 541008 | (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 541630 | (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 542779 | (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 542798 | (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 542850 | (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 542857 | (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 543160 | (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 547954 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800020671) | ||||
Ref 548308 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800024415) | ||||
Ref 548509 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026144) | ||||
Ref 526985 | Beyond 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 529213 | Proc 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 531034 | E6201, 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 532332 | Antitumor 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. |
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