1. MAPK/ERK Pathway
    Autophagy
  2. MEK
    Autophagy

MEK162 (Synonyms: Binimetinib; ARRY-162; ARRY-438162; MEK 162; ARRY 162; ARRY 438162)

Cat. No.: HY-15202 Purity: 98.61%
Handling Instructions

MEK162 is a potent and selective mitogen-activated protein kinase (MEK) inhibitor wirh IC50 of 12 nM.

For research use only. We do not sell to patients.
MEK162 Chemical Structure

MEK162 Chemical Structure

CAS No. : 606143-89-9

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10 mM * 1 mL in DMSO $66 In-stock
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Description

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].

Clinical Trial
Sponsor Condition Start Date Phase
Novartis AG Stage IV melanoma 2013-09-30 Phase 3
Novartis AG Stage III melanoma 2013-07-31 Phase 3
Novartis AG Stage IV melanoma 2013-07-31 Phase 3
Novartis AG Hematological neoplasm 2013-09-30 Phase 2
Novartis AG Stage IV melanoma 2013-09-30 Phase 2
References
Preparing Stock Solutions
Concentration Volume (DMSO) Mass 1 mg 5 mg 10 mg
1 mM 2.2664 mL 11.3320 mL 22.6639 mL
5 mM 0.4533 mL 2.2664 mL 4.5328 mL
10 mM 0.2266 mL 1.1332 mL 2.2664 mL
Cell Assay
[2]

MEK162 is dissolved in DMSO and stored, and then diluted with appropriate medium before use[2].

MCF7 cells infected as indicated are seeded in 12-well plates (2×104). After 24 hours, cells are treated with BEZ235 (100 or 200 nM), BKM120 (0.75 or 1 μM), GDC-0941 (1 μM), or MK2206 (2 μM) alone or in combination with MEK162 (1 μM), BI-D1870 (10 μM), or AZD6244 (1 μM), as indicated in text. Cell numbers are quantified by fixing cells with 4% glutaraldehyde or methanol, washing the cells twice in H2O, and staining the cells with 0.1% crystal violet. The dye is subsequently extracted with 10% acetic acid, and its absorbance is determined (570 nm). Growth curves are performed in triplicate. Viability assays with CellTiter-Glo are performed by plating 2,000 cells in 96-well plates, adding the drug at 24 hours, and assaying 4 to 5 days after drug addition. Cell-cycle and hypodiploid apoptotic cells are quantified by flow cytometry. Briefly, cells are washed with PBS, fixed in cold 70% ethanol, and then stained with propidium iodide while being treated with RNase. Quantitative analysis of sub-G1 cells is carried out in a FACScalibur cytometer using Cell Quest software[2].

Animal Administration
[1][2]

MEK162 is prepared in 0.5% Tween-80, 1% carboxymethyl cellulose.

Mice[2]
Six-week-old female athymic nude Foxn1nu mice are purchased from Harlan Laboratories. Mice are housed in air-filtered laminar flow cabinets with a 12-hour light/12-hour dark cycle and given food and water ad libitum. Mice are handled with aseptic procedures and allowed to acclimatize to local conditions for 1 week before the experimental manipulations. A 17β-estradiol pellet is implanted subcutaneously into each mouse 1 day before cell injection. 107 MCF-GFP or MCF7-RSK4 cells are resuspended in PBS/Matrigel (1:1) and injected subcutaneously into the right flank of each mouse in 200 μL of final volume. Treatments began when tumors reached an average size of 250 mm3 and are thus considered as established growing xenografts. Mice are treated once daily with placebo, BEZ235, BKM120, MK-2206, or MEK162 by oral gavage. BEZ235 (25-30 mg/kg, 6IW [6 days on 1 day off]) and BKM120 (30 mg/kg, 6IW) are dissolved in 10% NMP-90% PEG, freshly formulated, and administrated within 30 minutes. MK-2206 (100 mg/kg, 3IW) is formulated in 30% Captisol and MEK162 (6 mg/kg, BID) in 0.5% Tween-80, 1% carboxymethyl cellulose. For tumor growth studies, mice are treated for 7-24 days, depending on the xenograft model and treatment regime. Tumor xenografts are measured with calipers 3 times a week, and tumor volume is determined using the following formula: (length×width2)×(π/6). At the end of the experiment, the animals are anesthetized with 1.5% isofluorane-air mixture and killed by cervical dislocation. Tumors are removed 2 hours following the last administration.
Rat[1]
Rat collagen-induced arthritis (CIA) and rat adjuvant-induced arthritis (AIA) models are used to determine efficacy in the subacute inflammation setting. In the CIA studies, rats with established disease, induced by injections of Type II collagen, are treated with 0.3, 1 or 3 mg/kg ARRY-438162 (PO, BID) with or without 30 mg/kg ibuprofen (PO, QD) for six days. Body weight and ankle diameter are used to monitor disease progression on days 0-7. The AIA model is induced by an injection of a lipoidal amine in FCA on day 0. The AIA rats are treated with 1, 3 or 10 mg/kg ARRY-438162 (PO, QD) beginning on day 8 and continuing for 6 days, with or without the addition of 0.05 mg/kg methotrexate (PO, QD) which is dosed days 0-13. Disease progression is monitored on days 7-14 measuring both paw diameter and body weight.

References
M.Wt

441.23

Formula

C₁₇H₁₅BrF₂N₄O₃

CAS No.

606143-89-9

Storage
Powder -20°C 3 years
  4°C 2 years
In solvent -80°C 6 months
  -20°C 1 month
Shipping

Room temperature in continental US; may vary elsewhere

Solvent & Solubility

10 mM in DMSO

Purity: 98.61%

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MEK162
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