MEK is a member of kinases in MAPK signal pathway which can activates p38 MAPK and JNK when MEK is ACTIVATED by TNF-alpha, GPCR and so on. MEK could be regulated by MEKKs or RAF. The Raf / MEK / ERK signal transduction is involved in cell growth, cell proliferation and cell survival. [show the full text]
MEK Inhibitors
| Kat.nr. | Produktnamn | Information | Citeringar av produktanvändning | Produktvalideringar |
|---|---|---|---|---|
| S2673 | Trametinib (GSK1120212) | Trametinib (GSK1120212, JTP-74057) är en mycket specifik och potent MEK1/2-hämmare med IC50 på 0,92 nM/1,8 nM i cellfria analyser, och den hämmar inte kinasaktiviteterna hos c-Raf, B-Raf, ERK1/2. Denna förening aktiverar autophagy och inducerar apoptosis. |
|
|
| S1036 | PD0325901 (Mirdametinib) | Mirdametinib (PD0325901) är en selektiv och icke ATP-kompetitiv MEK-hämmare med ett IC50 på 0,33 nM i cellfria analyser, ungefär 500 gånger potentare än CI-1040 på fosforylering av ERK1 och ERK2. Fas 2. |
|
|
| S1008 | AZD6244 (Selumetinib) | Selumetinib (AZD6244, ARRY-142886) är en potent, mycket selektiv MEK-hämmare med IC50 på 14 nM för MEK1 och Kd-värde på 530 nM för MEK2. Den hämmar också ERK1/2-fosforylering med IC50 på 10 nM, ingen hämning av p38α, MKK6, EGFR, ErbB2, ERK2, B-Raf, etc. Selumetinib hämmar cellproliferation, migration och utlöser Apoptosis. Fas 3. |
|
|
| S8041 | Cobimetinib (GDC-0973) | Cobimetinib (GDC-0973, RG7420) är en potent och mycket selektiv MEK1-hämmare med IC50 på 4,2 nM, som visar ingen signifikant hämning när den testas mot en panel av mer än 100 serin-treonin- och tyrosinkinaser. Denna förening inducerar apoptos. Fas 3. |
|
|
| S7170 | Avutometinib (Ro5126766, CH5126766) | Avutometinib(RO5126766,CH5126766,VS 6766, CKI-27, R-7304, RG-7304) är en dubbel RAF/MEK-hämmare med IC50 på 8,2 nM, 19 nM, 56 nM och 160 nM för BRAF V600E, BRAF, CRAF respektive MEK1. Fas 1. |
|
|
| S1102 | U0126-EtOH | U0126-EtOH är en högselektiv hämmare av MEK1/2 med ett IC50-värde på 0,07 μM/0,06 μM i cellfria analyser, med 100 gånger högre affinitet för ΔN3-S218E/S222D MEK än PD98059. U0126 hämmar Autophagy och Mitophagy och uppvisar antiviral aktivitet. |
|
|
| S1177 | PD 98059 | PD98059 är en icke-ATP-kompetitiv MEK-hämmare med IC50 på 2 μM i en cellfri analys, som specifikt hämmar MEK-1-medierad aktivering av MAPK; hämmar inte direkt ERK1 eller ERK2. PD98059 är en ligand för aryl hydrocarbon receptor (AHR) och fungerar som en AHR-antagonist. |
|
|
| S1020 | CI-1040 (PD184352) | PD184352 (CI-1040) är en ATP-icke-kompetitiv MEK1/2-hämmare med en IC50 på 17 nM i cellbaserade analyser, 100 gånger mer selektiv för MEK1/2 än MEK5. PD184352 (CI-1040) inducerar selektivt apoptos. |
|
|
| S7007 | MEK162 (Binimetinib, ARRY-162) | Binimetinib (MEK162, ARRY-162, ARRY-438162) är en potent hämmare av MEK1/2 med IC50 på 12 nM i en cellfri analys. Binimetinib inducerar G1-cellcykelarrest och apoptos i humana NSCLC-cellinjer och inducerar autophagy. Fas 3. |
|
|
| S1531 | (E/Z)-BIX02189 | (E/Z)-BIX02189 är en selektiv hämmare av MEK5 med ett IC50 på 1,5 nM, och hämmar även ERK5 katalytisk aktivitet med ett IC50 på 59 nM i cellfria analyser, och hämmar inte närbesläktade kinaser MEK1, MEK2, ERK2 och JNK2. |
|
|
In the mitogen-activated protein kinase (MAPK) pathway, receptor tyrosine kinase activation results in adaptor proteins phosphorylating RAS. This results in the activation of the RAF-MEK-ERK kinase signalling pathway, and consequently leads to the activation of several downstream substrates that affect a number of transcription factors. The knock-on effect is that a myriad of cellular processes such as cell proliferation, survival, transformation, translational control and cytoskeletal rearrangement. In oncology, the MAPK pathway is a key contributor to tumor progression, angiogenesis, and metastasis.
In the RAS-RAF-MEK-ERK pathway, MEK has been the target of oncology research. The MEK kinase is expressed from MEK1 and MEK2 – two genes that share ~80% structural homology – that display slightly different isoforms of MEK to produce potentially different functions. Both MEK1 and MEK2 kinases are implicated in ~30% of all human cancers where MAPK signalling pathway is involved.[1] These dual-specificity kinases phosphorylate both tyrosine and threonine residues; MEK1 and MEK2 sequentially phosphorylate ERK1 at 185Tyr and then at 183Thr. MEK exists just downstream of RAF in the classical MAPK pathway known as RAS-RAF-MEK-ERK pathway. Phosphorylation of MEK by RAF results in the phosphorylation of ERK1 and ERK2. MEK kinases show very high specificity for ERK, in fact it is the only known substrate for MEK. Therefore, constitutive phosphorylation of MEK in the RAF-MEK-ERK kinase pathway occurs by either the overexpression or mutation of receptor tyrosine kinases, and/or mutations of RAS and RAF (A-RAF and B-RAF).[2]
The MEK enzyme itself consists of hydrophobic allosteric pockets adjacent to the ATP-binding site that facilitates the design of highly selective allosteric inhibitors. This is in contRASt to the many kinases for which there is no allosteric-binding site. Consequently, this feature is recognized by many pharmaceutical companies as a characteristic that facilitates more selective inhibitor design since the more conserved ATP-binding site is not directly targeted. MEK1 and MEK2 are positioned at the focal point of many mitogenic signaling pathways that integrates into the ERK pathway. Characteristics such as unusually restricted and unique substrate specificities, plus the integrating role of mitogenic signaling pathways demonstrates the benefits of developing a MEK inhibitor against the ERK pathway.[3]
The utility of targeting MEK inhibition is likely to be best realized among tumors where the MEK pathway is constitutively activated. Such a scenario includes activating mutations of BRAF that results in tumors that are dependent to MEK signaling, and consequently very sensitive to MEK inhibition.[4] This is likely to be the case among a sub-population of BRAF mutations observed in melanoma and thyroid cancers. Currently, MEK inhibition is likely to prove most effective when used in a combination strategy. This is because there is cross-talk involved between RAS-RAF-MEK-ERK and the PI3K-AKT pathway. As a consequence, inhibition of one pathway leads to constitutive signalling in the other. This is a reflection of the complexity of the kinase signalling pathways implicated in cancer.[2]
Aside from anti-tumor potential, MEK inhibition may play a role where inflammation is concerned. Several key protein downstream of MEK are involved in inflammatory responses including TNF, IL-1, and other cytokines. MEK signaling directly impacts both the expression of cytokines and subsequent activation pathways. Therefore, MEK inhibitors –particularly orally bioavailable compounds – may be suitable agents for the treatment of inflammatory disease. In addition, it should be noted that anaphylatoxins utilize the MEK kinase cascade to initiate disease processes such as arthritis.[2]
Produkterna är endast avsedda för forskning. Ej för användning på människor. Vi säljer inte till patienter.
©Copyright 2013 Selleck Chemicals. Med ensamrätt.