CEP-32496

"目录号: HY-15202

MAPK/ERK Pathway Autophagy-

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。

MEK Autophagy

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

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)

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