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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]
| Cat.No. | Product Name | Information | Product Use Citations | Product Validations |
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| S2673 | Trametinib (GSK1120212) | Trametinib (GSK1120212, JTP-74057) is a highly specific and potent MEK1/2 inhibitor with IC50 of 0.92 nM/1.8 nM in cell-free assays, and it does not inhibit the kinase activities of c-Raf, B-Raf, ERK1/2. This compound activates autophagy and induces apoptosis. |
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| S1036 | PD0325901 (Mirdametinib) | Mirdametinib (PD0325901) is a selective and non ATP-competitive MEK inhibitor with IC50 of 0.33 nM in cell-free assays, roughly 500-fold more potent than CI-1040 on phosphorylation of ERK1 and ERK2. Phase 2. |
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| S1008 | AZD6244 (Selumetinib) | Selumetinib (AZD6244, ARRY-142886) is a potent, highly selective MEK inhibitor with IC50 of 14 nM for MEK1 and Kd value of 530 nM for MEK2. It also inhibits ERK1/2 phosphorylation with IC50 of 10 nM, no inhibition to p38α, MKK6, EGFR, ErbB2, ERK2, B-Raf, etc. Selumetinib suppresses cell proliferation, migration and trigger apoptosis. Phase 3. |
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| S8041 | Cobimetinib (GDC-0973) | Cobimetinib (GDC-0973, RG7420) is a potent and highly selective MEK1 inhibitor with IC50 of 4.2 nM, showing no significant inhibition when tested against a panel of more than 100 serine-threonine and tyrosine kinases. This compound induces apoptosis. Phase 3. |
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| S7170 | Avutometinib (Ro5126766, CH5126766) | Avutometinib(RO5126766,CH5126766,VS 6766, CKI-27, R-7304, RG-7304) is a dual RAF/MEK inhibitor with IC50 of 8.2 nM,19 nM, 56 nM, and 160 nM for BRAF V600E, BRAF, CRAF, and MEK1, respectively. Phase 1. |
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| S1102 | U0126-EtOH | U0126-EtOH is a highly selective inhibitor of MEK1/2 with IC50 of 0.07 μM/0.06 μM in cell-free assays, 100-fold higher affinity for ΔN3-S218E/S222D MEK than PD98059. U0126 inhibits autophagy and mitophagy with antiviral activity. |
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| S1177 | PD98059 | PD98059 is a non-ATP competitive MEK inhibitor with IC50 of 2 μM in a cell-free assay, specifically inhibits MEK-1-mediated activation of MAPK; does not directly inhibit ERK1 or ERK2. This compound is a ligand for the aryl hydrocarbon receptor (AHR) and functions as an AHR antagonist. |
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| S1020 | PD184352 (CI-1040) | PD184352 (CI-1040) is an ATP non-competitive MEK1/2 inhibitor with IC50 of 17 nM in cell-based assays, 100-fold more selective for MEK1/2 than MEK5. This compound selectively induces apoptosis. |
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| S7007 | Binimetinib (MEK162) | Binimetinib (MEK162, ARRY-162, ARRY-438162) is a potent inhibitor of MEK1/2 with IC50 of 12 nM in a cell-free assay. It induces G1 cell cycle arrest and apoptosis in human NSCLC cell lines and also triggers autophagy. Phase 3. |
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| S1531 | BIX 02189 | BIX02189 is a selective inhibitor of MEK5 with IC50 of 1.5 nM, also inhibits ERK5 catalytic activity with IC50 of 59 nM in cell-free assays, and does not inhibit closely related kinases MEK1, MEK2, ERK2, and JNK2. |
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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]
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