MEK162 | CAS:606143-89-9

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Name:MEK162; Binimetinib; ARRY-162; ARRY-438162
Cat. No. :CS-0627
CAS No. :606143-89-9
Formula:C17H15BrF2N4O3
M. Wt. : 441.23
Solubility:10 mM in DMSO

MEK162 is a potent and selective mitogen-activated protein kinase (MEK) inhibitor wirh IC50 of 12 nM. IC50 & Target: IC50: 12 nM (MEK)[1]In Vitro: In MCF7 cells, RSK3 or RSK4 expression decreases response to treatment with any of the PI3K inhibitors alone. However, the combination of PI3K inhibition with MEK162 or BI-D1870 completely reverses the resistance of RSK-expressing cells[2]. MEK162 blocks basal ERK phosphorylation in all HRAS mutant cell lines. The combination of Everolimus and AZD6244/MEK162 causes a stronger inhibition of S6 kinase than single use of Everolimus on Western blot. The combination of Everolimus and AZD6244/MEK162 also translated in a stronger blockade of cell growth in HRAS mutant cells than single use. MEK162 shows stronger synergism with Everolimus than AZD6244[3].In Vivo: Treatment with MEK162 (ARRY-438162) reduces disease severity in a dose-related manner in both animal models. ARRY-438162 in the CIA model inhibits increases in ankle diameter by 27% and 50% at 1 and 3 mg/kg, while Ibuprofen has 46% inhibition. When combined with Ibuprofen, these same two doses result in 74% and 72% inhibition, respectively. Microscopic examination of the ankle joints show ARRY-438162 significantly inhibits lesions (inflammation, cartilage damage, pannus formation and bone resorption) by 32% and 60% at 1 and 3 mg/kg, while treatment with Ibuprofen alone results in 17% inhibition, which is not significantly different from the controls. When these two doses of ARRY-438162 are combined with ibuprofen, the result is 54% and 77% inhibition of joint destruction. In AIA, 3 and 10 mg/kg of ARRY-438162 inhibit AIA ankle diameter 11% and 34%, while MTX has 33% inhibition. When combined with MTX, 3 and 10 mg/kg of ARRY-438162 result in 55% and 71% inhibition. Microscopic examination of ankle joints for inflammation and bone resorption also shows improved efficacy versus either compound alone[1]. When MEK162 is combined with BEZ235, a significant reduction of tumor growth is observed (P=0.01). This increase in antitumor activity is accompanied by a decrease in phospho-ERK and phospho-S6 staining. No significant changes are observed in phospho-4EBP1 staining, a direct target of mTOR activity[2].

Kiessling MK, et al. Mutant HRAS as novel target for MEK and mTOR inhibitors. Oncotarget. 2015 Dec 8;6(39):42183-96. J Pheneger, et al. 2006, ACR Annual Scientific Meeting. Abst 794. Cheng H, et al. PIK3CA(H1047R)- and Her2-initiated mammary tumors escape PI3K dependency by compensatory activation of MEK-ERK signaling. Oncogene. 2016 Jun 9;35(23):2961-70. Seip K, et al. Fibroblast-induced switching to the mesenchymal-like phenotype and PI3K/mTOR signaling protects melanoma cells from BRAF inhibitors. Oncotarget. 2016 Apr 12;7(15):19997-20015. Serra V, et al. RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer. J Clin Invest, 2013, 123(6), 2551-2563.