1. MAPK/ERK Pathway
    Autophagy
  2. MEK
    Autophagy

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

Cat. No.: HY-15202 Purity: 98.61%
Data Sheet SDS 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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    MEK162 purchased from MCE. Usage Cited in: Oncogene. 2016 Jun 9;35(23):2961-70.

    The combined use of MEK162 with HER kinase inhibitor Lapatinib, almost completely abolishes MAPK signaling as evidenced by diminished phospho-Erk levels. Western blot analyses of ERK signaling in tumor transplants from mice treated as indicated. Three hours after their dose on day four of treatment, the mice are sacrificed for analysis. Vinculin is used as a loading control.

    MEK162 purchased from MCE. Usage Cited in: Oncogene. 2016 Jun 9;35(23):2961-70.

    Western blot analysis of p-AKT(T308), p-AKT(S473) and p-ERK in transplanted NIC+PIK3CAH1047R tumors treated as indicated. Transplants of NIC+PIK3CAH1047R primary mammary tumors are first established in immunodeficient nude mice maintained on Doxycycline. Treatment starts when tumor transplants reach 500 mm3. DOX On, on Doxycycline; DOX Off, Doxycycline withdrawal. Lapatinib, 100mg/kg/day, p.o; GDC-0941, 120mg/kg/ day, p.o. Tumo

    MEK162 purchased from MCE. Usage Cited in: Oncotarget. 2017 Feb 28;8(9):14835-14846.

    MEK inhibition results in reduced ERK phosphorylation.A. Western blot analysis of SEM and KOPN8 exposed to 500 nM of MEK inhibitor or vehicle control (DMSO) for 6, 24 and 48 hours. Both cell lines almost completely lose ERK phosphorylation (p-ERK), while total ERK (t-ERK) levels remain unaffected. B. Analysis of MEK phosphorylation (p-MEK) suggests exposure to MEK162 and Selumetinib results in enhanced MEK phosphorylation in both cell lines, whereas total MEK (t-MEK) levels remain constant.
    • Biological Activity

    • Protocol

    • Technical Information

    • Purity & Documentation

    • References

    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
    NCT Number Sponsor Condition Start Date Phase
    NCT00959127 Array BioPharma Advanced Solid Tumors|Advanced or Metastatic Biliary Cancer|Metastatic Colorectal Cancer August 2009 Phase 1
    NCT00650767 Array BioPharma Rheumatoid Arthritis March 2008 Phase 2
    NCT03170206 Dana-Farber Cancer Institute|Pfizer|Array BioPharma Lung Cancer May 29, 2017 Phase 1|Phase 2
    NCT02964689 Swiss Group for Clinical Cancer Research Advanced Non-small Cell Lung Cancer|KRAS Gene Mutation|Lung Cancer April 12, 2017 Phase 1
    NCT02185690 University Health Network, Toronto|Novartis Pharmaceuticals Lungcancer March 2017 Phase 1
    NCT03106415 Mayo Clinic|National Cancer Institute (NCI) Breast Adenocarcinoma|Estrogen Receptor Negative|HER2/Neu Negative|Progesterone Receptor Negative|Stage III Breast Cancer|Stage IIIA Breast Cancer|Stage IIIB Breast Cancer|Stage IIIC Breast Cancer|Stage IV Breast Cancer|Triple-Negative Breast Carcinoma July 28, 2017 Phase 1|Phase 2
    NCT02451865 Jonsson Comprehensive Cancer Center|National Cancer Institute (NCI) Recurrent Non-Small Cell Lung Carcinoma|Stage IV Non-Small Cell Lung Cancer June 2016 Phase 1
    NCT02263898 Jonsson Comprehensive Cancer Center|National Cancer Institute (NCI) Recurrent Melanoma|Stage IV Melanoma January 2015 Phase 2
    NCT02834364 University of Heidelberg Medical Center|Array BioPharma|German Cancer Research Center|Coordinating Centre for Clinical Trials Heidelberg|University Hospital Heidelberg Relapsed or Refractory Multiple Myeloma|Patients With BRAFV600 E or BRAFV600K Mutation June 2016 Phase 2
    NCT02902042 Prof. Dr. med. Dirk Schadendorf|University Hospital, Essen Malignant Melanoma December 2016 Phase 1|Phase 2
    NCT02928224 Array BioPharma|Merck KGaA|Pierre Fabre Medicament BRAF V600E-mutant Metastatic Colorectal Cancer August 2016 Phase 3
    NCT02510001 University of Oxford|Queen's University, Belfast|Oxford University Hospitals NHS Trust|Velindre NHS Trust|University Hospital, Antwerp|Hospital Vall d'Hebron|Hopital St Antoine, Paris|European Georges Pompidou Hospital|Pfizer|University of Turin, Italy|Belfast Health and Social Care Trust|Beaumont Hospital|European Commission|Array BioPharma|Q2 solutions|Covance|QPS Holdings Solid Tumour|Colorectal Cancer November 2014 Phase 1
    NCT02465060 National Cancer Institute (NCI) Advanced Malignant Solid Neoplasm|Bladder Carcinoma|Breast Carcinoma|Cervical Carcinoma|Colon Carcinoma|Colorectal Carcinoma|Endometrial Carcinoma|Esophageal Carcinoma|Gastric Carcinoma|Glioma|Head and Neck Carcinoma|Kidney Carcinoma|Liver and Intrahepatic Bile Duct Carcinoma|Lung Carcinoma|Lymphoma|Malignant Uterine Neoplasm|Melanoma|Ovarian Carcinoma|Pancreatic Carcinoma|Plasma Cell Myeloma|Prostate Carcinoma|Rectal Carcinoma|Recurrent Bladder Carcinoma|Recurrent Breast Carcinoma|Recurrent Cer August 12, 2015 Phase 2
    NCT00959127 Array BioPharma Advanced Solid Tumors|Advanced or Metastatic Biliary Cancer|Metastatic Colorectal Cancer August 2009 Phase 1
    NCT00650767 Array BioPharma Rheumatoid Arthritis March 2008 Phase 2
    NCT03170206 Dana-Farber Cancer Institute|Pfizer|Array BioPharma Lung Cancer May 29, 2017 Phase 1|Phase 2
    NCT02964689 Swiss Group for Clinical Cancer Research Advanced Non-small Cell Lung Cancer|KRAS Gene Mutation|Lung Cancer April 12, 2017 Phase 1
    NCT02185690 University Health Network, Toronto|Novartis Pharmaceuticals Lungcancer March 2017 Phase 1
    NCT03106415 Mayo Clinic|National Cancer Institute (NCI) Breast Adenocarcinoma|Estrogen Receptor Negative|HER2/Neu Negative|Progesterone Receptor Negative|Stage III Breast Cancer|Stage IIIA Breast Cancer|Stage IIIB Breast Cancer|Stage IIIC Breast Cancer|Stage IV Breast Cancer|Triple-Negative Breast Carcinoma July 28, 2017 Phase 1|Phase 2
    NCT02451865 Jonsson Comprehensive Cancer Center|National Cancer Institute (NCI) Recurrent Non-Small Cell Lung Carcinoma|Stage IV Non-Small Cell Lung Cancer June 2016 Phase 1
    NCT02263898 Jonsson Comprehensive Cancer Center|National Cancer Institute (NCI) Recurrent Melanoma|Stage IV Melanoma January 2015 Phase 2
    NCT02834364 University of Heidelberg Medical Center|Array BioPharma|German Cancer Research Center|Coordinating Centre for Clinical Trials Heidelberg|University Hospital Heidelberg Relapsed or Refractory Multiple Myeloma|Patients With BRAFV600 E or BRAFV600K Mutation June 2016 Phase 2
    NCT02902042 Prof. Dr. med. Dirk Schadendorf|University Hospital, Essen Malignant Melanoma December 2016 Phase 1|Phase 2
    NCT02928224 Array BioPharma|Merck KGaA|Pierre Fabre Medicament BRAF V600E-mutant Metastatic Colorectal Cancer August 2016 Phase 3
    NCT02510001 University of Oxford|Queen's University, Belfast|Oxford University Hospitals NHS Trust|Velindre NHS Trust|University Hospital, Antwerp|Hospital Vall d'Hebron|Hopital St Antoine, Paris|European Georges Pompidou Hospital|Pfizer|University of Turin, Italy|Belfast Health and Social Care Trust|Beaumont Hospital|European Commission|Array BioPharma|Q2 solutions|Covance|QPS Holdings Solid Tumour|Colorectal Cancer November 2014 Phase 1
    NCT02465060 National Cancer Institute (NCI) Advanced Malignant Solid Neoplasm|Bladder Carcinoma|Breast Carcinoma|Cervical Carcinoma|Colon Carcinoma|Colorectal Carcinoma|Endometrial Carcinoma|Esophageal Carcinoma|Gastric Carcinoma|Glioma|Head and Neck Carcinoma|Kidney Carcinoma|Liver and Intrahepatic Bile Duct Carcinoma|Lung Carcinoma|Lymphoma|Malignant Uterine Neoplasm|Melanoma|Ovarian Carcinoma|Pancreatic Carcinoma|Plasma Cell Myeloma|Prostate Carcinoma|Rectal Carcinoma|Recurrent Bladder Carcinoma|Recurrent Breast Carcinoma|Recurrent Cer August 12, 2015 Phase 2
    NCT02089230 M.D. Anderson Cancer Center|Array BioPharma Leukemia August 2014 Phase 1|Phase 2
    NCT02105350 University Health Network, Toronto Biliary Tract Carcinoma|Gallbladder Carcinoma June 2015 Phase 1
    NCT02094872 Yale University|National Cancer Institute (NCI) Recurrent Melanoma|Stage IIIA Melanoma|Stage IIIB Melanoma|Stage IIIC Melanoma|Stage IV Melanoma May 2014 Phase 2
    NCT02050815 Array BioPharma Hepatic Impairment March 2014 Phase 1
    NCT01885195 Array BioPharma Solid Tumor and Hematologic Malignancies October 2013 Phase 2
    NCT02773459 Seoul National University Hospital Biliary Tract Cancer April 2016 Phase 1|Phase 2
    NCT02613650 University of Utah|Array BioPharma Advanced KRAS Positive Metastatic Colorectal Cancer May 12, 2016 Phase 1
    NCT01469130 Array BioPharma Advanced Solid Tumor November 2011 Phase 1
    NCT03158103 Memorial Sloan Kettering Cancer Center|Array BioPharma|Plexxikon Gastrointestinal Stromal Tumor (GIST) April 15, 2017 Phase 1
    NCT01449058 Array BioPharma Advanced and Selected Solid Tumors, AML, High Risk and Very High Risk MDS March 2012 Phase 1|Phase 2
    NCT01556568 Array BioPharma Cardiomegaly February 2012 Phase 2
    NCT01562899 Array BioPharma Metastatic Pancreatic Adenocarcinoma|BRAF Mutated Melanoma August 2012 Phase 2
    NCT01828034 Memorial Sloan Kettering Cancer Center|Array BioPharma Advanced Biliary Tract Carcinoma April 2013 Phase 1|Phase 2
    NCT02285439 Children's Hospital Los Angeles|Dana-Farber Cancer Institute Low-Grade Gliomas|Malignant Neoplasms, Brain|Soft Tissue Neoplasms April 2016 Phase 1|Phase 2
    NCT01801358 Array BioPharma Uveal Melanoma August 2013 Phase 1|Phase 2
    NCT01320085 Array BioPharma BRAF or NRAS Mutant Metastatic Melanoma March 2011 Phase 2
    NCT01352273 Array BioPharma Advanced Solid Tumors June 2011 Phase 1
    NCT02049801 Bruno C. Medeiros|National Cancer Institute (NCI)|Stanford University Adult Acute Minimally Differentiated Myeloid Leukemia (M0)|Adult Acute Monoblastic Leukemia (M5a)|Adult Acute Monocytic Leukemia (M5b)|Adult Acute Myeloblastic Leukemia With Maturation (M2)|Adult Acute Myeloblastic Leukemia Without Maturation (M1)|Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities|Adult Acute Myeloid Leukemia With Del(5q)|Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)|Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)|Adult Acute Myeloid Leukemia With t(16;16)(p13; December 2014 Phase 1
    NCT01337765 Array BioPharma Unspecified Adult Solid Tumor, Protocol Specific|Solid Tumor July 2011 Phase 1
    NCT01363232 Array BioPharma Advanced Solid Tumors|Selected Solid Tumors August 2011 Phase 1
    NCT01991379 Memorial Sloan Kettering Cancer Center|Array BioPharma|University of Pittsburgh Gastrointestinal Stromal Tumor (GIST) November 2013 Phase 1|Phase 2
    NCT02041481 City of Hope Medical Center|National Cancer Institute (NCI)|Array BioPharma Recurrent Colon Cancer|Recurrent Rectal Cancer|Stage IVA Colon Cancer|Stage IVA Rectal Cancer|Stage IVB Colon Cancer|Stage IVB Rectal Cancer June 2014 Phase 1
    NCT01763164 Array BioPharma Metastatic or Unresectable Cutaneous Melanoma July 2013 Phase 3
    NCT01909453 Array BioPharma Melanoma September 2013 Phase 3
    NCT01859026 H. Lee Moffitt Cancer Center and Research Institute|Array BioPharma Lung Cancer|Non-Small Cell Lung Cancer December 10, 2013 Phase 1
    NCT01781572 Array BioPharma Locally Advanced or Metastatic NRAS Mutant Melanoma June 2013 Phase 1|Phase 2
    NCT01543698 Array BioPharma Solid Tumors Harboring a BRAF V600 Mutation May 2012 Phase 1|Phase 2
    NCT01927341 Array BioPharma Metastatic Colorectal Cancer November 2013 Phase 1|Phase 2
    NCT02276027 Novartis Pharmaceuticals|Novartis Adenocarcinoma Lung Cancer; Squamous Cell Lung Carcinoma January 20, 2015 Phase 2
    NCT02159066 Array BioPharma Melanoma July 2014 Phase 2
    NCT01649336 Array BioPharma Epithelial Ovarian Cancer|Fallopian Tube Cancer|Peritoneal Cancer July 2012 Phase 1
    NCT01849874 Array BioPharma Low-grade Serous Ovarian Cancer|Low-grade Serous Fallopian Tube Cancer|Low-grade Serous Peritoneal Cancer June 2013 Phase 3
    NCT02631447 Fondazione Melanoma Onlus|Clinical Research Technology S.r.l. Metastatic Melanoma November 2016 Phase 2
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    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]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    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. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    References
    Molecular Weight

    441.23

    Formula

    C₁₇H₁₅BrF₂N₄O₃

    CAS No.

    606143-89-9

    Storage

    Please store the product under the recommended conditions in the Certificate of Analysis.

    Shipping

    Room temperature in continental US; may vary elsewhere

    Solvent & Solubility

    10 mM in DMSO

    MEK162 is dissolved in 1% carboxymethyl cellulose/0.5%Tween 80[4].
    MEK162 is dissolved in DMSO and further diluted in 0.5% metylcellulose[5].

    * "<1 mg/mL" means slightly soluble or insoluble. "≥" means soluble, but saturation unknown.

    References

    Purity: 98.61%

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    MEK162
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