"目录号: HY-15202
MEK162 是一种有效的选择性的丝裂原活化蛋白激酶 (MEK) 抑制剂，IC50为 12 nM。
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生物活性
Description
MEK162 is a potent and selective mitogen-activated protein kinase (MEK) inhibitor wirhIC50of 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
Array BioPharma
Advanced Solid Tumors-Advanced or Metastatic Biliary Cancer-Metastatic Colorectal Cancer
August 2009
Phase 1
Array BioPharma
Rheumatoid Arthritis
March 2008
Phase 2
Dana-Farber Cancer Institute-Pfizer-Array BioPharma
Lung Cancer
May 29, 2017
Phase 1-Phase 2
Swiss Group for Clinical Cancer Research
Advanced Non-small Cell Lung Cancer-KRAS Gene Mutation-Lung Cancer
April 12, 2017
Phase 1
University Health Network, Toronto-Novartis Pharmaceuticals
Lungcancer
March 2017
Phase 1
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
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
Jonsson Comprehensive Cancer Center-National Cancer Institute (NCI)
Recurrent Melanoma-Stage IV Melanoma
January 2015
Phase 2
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
Prof. Dr. med. Dirk Schadendorf-University Hospital, Essen
Malignant Melanoma
December 2016
Phase 1-Phase 2
Array BioPharma-Merck KGaA-Pierre Fabre Medicament
BRAF V600E-mutant Metastatic Colorectal Cancer
August 2016
Phase 3
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
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
Array BioPharma
Advanced Solid Tumors-Advanced or Metastatic Biliary Cancer-Metastatic Colorectal Cancer
August 2009
Phase 1
Array BioPharma
Rheumatoid Arthritis
March 2008
Phase 2
Dana-Farber Cancer Institute-Pfizer-Array BioPharma
Lung Cancer
May 29, 2017
Phase 1-Phase 2
Swiss Group for Clinical Cancer Research
Advanced Non-small Cell Lung Cancer-KRAS Gene Mutation-Lung Cancer
April 12, 2017
Phase 1
University Health Network, Toronto-Novartis Pharmaceuticals
Lungcancer
March 2017
Phase 1
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
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
Jonsson Comprehensive Cancer Center-National Cancer Institute (NCI)
Recurrent Melanoma-Stage IV Melanoma
January 2015
Phase 2
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
Prof. Dr. med. Dirk Schadendorf-University Hospital, Essen
Malignant Melanoma
December 2016
Phase 1-Phase 2
Array BioPharma-Merck KGaA-Pierre Fabre Medicament
BRAF V600E-mutant Metastatic Colorectal Cancer
August 2016
Phase 3
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
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
M.D. Anderson Cancer Center-Array BioPharma
Leukemia
August 2014
Phase 1-Phase 2
University Health Network, Toronto
Biliary Tract Carcinoma-Gallbladder Carcinoma
June 2015
Phase 1
Yale University-National Cancer Institute (NCI)
Recurrent Melanoma-Stage IIIA Melanoma-Stage IIIB Melanoma-Stage IIIC Melanoma-Stage IV Melanoma
May 2014
Phase 2
Array BioPharma
Hepatic Impairment
March 2014
Phase 1
Array BioPharma
Solid Tumor and Hematologic Malignancies
October 2013
Phase 2
Seoul National University Hospital
Biliary Tract Cancer
April 2016
Phase 1-Phase 2
University of Utah-Array BioPharma
Advanced KRAS Positive Metastatic Colorectal Cancer
May 12, 2016
Phase 1
Array BioPharma
Advanced Solid Tumor
November 2011
Phase 1
Memorial Sloan Kettering Cancer Center-Array BioPharma-Plexxikon
Gastrointestinal Stromal Tumor (GIST)
April 15, 2017
Phase 1
Array BioPharma
Advanced and Selected Solid Tumors, AML, High Risk and Very High Risk MDS
March 2012
Phase 1-Phase 2
Array BioPharma
Cardiomegaly
February 2012
Phase 2
Array BioPharma
Metastatic Pancreatic Adenocarcinoma-BRAF Mutated Melanoma
August 2012
Phase 2
Memorial Sloan Kettering Cancer Center-Array BioPharma
Advanced Biliary Tract Carcinoma
April 2013
Phase 1-Phase 2
Children's Hospital Los Angeles-Dana-Farber Cancer Institute
Low-Grade Gliomas-Malignant Neoplasms, Brain-Soft Tissue Neoplasms
April 2016
Phase 1-Phase 2
