生物活性

• 靶点

  MEK1 IC50:12nM

  MEK2 IC50:12nM

• 描述MEKs, which are members of the MAPKK family, can activate both ERK1 and ERK2 by catalyzing the phosphorylation on T202/Y204. Also MEK itself can be phosphorylated and activated through Ras when the upstream signaling is activated by extracellular stimuli, including growth factors, hormones etc.. ARRY-162 is a potent inhibitor of MEK with IC₅₀ value of 12 nM^[1]. A cellular study showed that a panel of NSCLC cells with K-ras mutation, including Calu-1, H1792, H358, H23, H460, A549 and H157 cell lines, were relatively sensitive to ARRY-162 with IC₅₀<5 μM, which suggested that Ras mutant may respond better to ARRY-162. Treatment with ARRY-162 induced G1 arrest at concentration of 0.5 μM and 1 μM, apoptosis and autophagy at concentration of 1 μM and 3 μM for 48 h in A549 and H157 cells with K-ras mutation, but not in H522 cells (without K-ras mutation). A further signaling study indicated that ARRY-162 can effectively inhibit MEK/ERK signaling regardless of cell sensitivity as decreased p-ERK can be observed both in the ARRY-162-sensitive and -resistant cells. For MEK inhibition may activate Akt signaling, ARRY-162 at low concentration (0.5 μM-1 μM in different cell lines) increased p-AKT and its downstream p-PRAS40 and p-GSK3 in A549, H522 and ARRY-162-resistant EKVT cells, irrespective of their sensitivity to ARRY-162. Also, the suppression of p-S6 in mTOR signaling, but not p-70S6K or p-4EBP1, is associated with the increased cell sensitivity to ARRY-162. All these suggested the inhibition of PI3K pathway may have synergy with inhibition of MEK/ERK pathway by ARRY-162 in cell growth sensitivity. As prediction, combined oral treatment with 5 mg/kg ARRY-162 and 7.5 mg/kg BMK120 suppressed the tumor growth in A549 xenografts, markedly augmented the effect on tumor growth by the agent alone.^[1]
• 作用机制ARRY-162 is an ATP-uncompetitive inhibitor of MEK.^[1]

• 动物研究
  剂量	Mice: min = 6 mg/kg[2] (p.o.), max = 30 mg/kg[4] (p.o.)
  给药途径	p.o.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02041481	Recurrent Colon Cancer ... more >> Recurrent Rectal Cancer Stage IVA Colon Cancer Stage IVA Rectal Cancer Stage IVB Colon Cancer Stage IVB Rectal Cancer Collapse <<	Phase 1	Completed	-	United States, California ... more >> City of Hope Medical Center Duarte, California, United States, 91010 Collapse <<
  NCT02465060	Advanced Malignant Solid Neopl... more >>asm 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 Cervical Carcinoma Recurrent Colon Carcinoma Recurrent Colorectal Carcinoma Recurrent Esophageal Carcinoma Recurrent Gastric Carcinoma Recurrent Glioma Recurrent Head and Neck Carcinoma Recurrent Liver Carcinoma Recurrent Lung Carcinoma Recurrent Lymphoma Recurrent Malignant Solid Neoplasm Recurrent Melanoma Recurrent Ovarian Carcinoma Recurrent Pancreatic Carcinoma Recurrent Plasma Cell Myeloma Recurrent Prostate Carcinoma Recurrent Rectal Carcinoma Recurrent Skin Carcinoma Recurrent Thyroid Gland Carcinoma Recurrent Uterine Corpus Carcinoma Refractory Lymphoma Refractory Malignant Solid Neoplasm Refractory Plasma Cell Myeloma Skin Carcinoma Thyroid Gland Carcinoma Uterine Corpus Cancer Collapse <<	Phase 2	Recruiting	-	-
  NCT02049801	Adult Acute Minimally Differen... more >>tiated 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;q22) Adult Acute Myeloid Leukemia With t(8;21)(q22;q22) Adult Acute Myelomonocytic Leukemia (M4) Adult Erythroleukemia (M6a) Adult Pure Erythroid Leukemia (M6b) Recurrent Adult Acute Myeloid Leukemia Collapse <<	Phase 1	Terminated(logistics)	-	United States, California ... more >> Stanford University, School of Medicine Stanford, California, United States, 94305 Collapse <<

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• 参考文献

• [1] Yao W, Yue P, et al. Enhancing therapeutic efficacy of the MEK inhibitor, MEK162, by blocking autophagy or inhibiting PI3K/Akt signaling in human lung cancer cells. Cancer Lett. 2015 Aug 1;364(1):70-8.

  [2] Serra V, Eichhorn PJ, et al. RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer. J Clin Invest. 2013;123(6):2551-63.

  [3] Patrice A. Lee, Eli Wallace, et al. Preclinical Development of ARRY-162, A Potent and Selective MEK 1/2 Inhibitor. Cancer Res 2010;70(8 Suppl):Abstract nr 2515.