Selumetinib, Free Base **

产品名称：Selumetinib, Free Base
产品货号：LC  S-4490
产品规格：100 MG
Selumetinib, also known as AZD6244, is a specific MEK1/2 inhibitor with an IC50 value of 14 nM against purified MEK1.  Yeh, T.C., et al.  "Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor."  Clin. Cancer Res. 13:  1576-1583 (2007).
Selumetinib inhibited the growth of primary hepatocellular carcinoma (HCC) cells in vitro and the growth of 7 HCC xenografts dose-dependently in vivo, possibly by inactivating ERK1/2 and p90RSK and up-regulating activated caspase-3, caspase-7 and cleaved poly(ADP)ribose polymerase.  Huynh, H., et al.  "Targeted inhibition of the extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) in the treatment of hepatocellular carcinoma."  Mol. Cancer Ther. 6:  138-146 (2007).
The combination of selumetinib and MK2206 at ratios of 8:1, 4:1, and 2:1 has a significant synergistic inhibitory effect on the growth of human non-small cell lung cancer in vitro and in vivo and improves the survival of mice bearing highly aggressive human lung tumors.  Meng, J., et al.  "Combination treatment with MEK and AKT inhibitors is more effective than each drug alone in human non-small cell lung cancer in vitro and in vivo."  PLoS One 5:  e14124 (2010).
Selumetinib and the mTOR inhibitor rapamycin had synergistic inhibitory effects on the growth of BxPC-3 and MIA PaCa-2 pancreatic cancers in vivo.  Selumetinib also demonstrated a significant anti-angiogenic effect.  Chang, Q., et al.  "Effects of combined inhibition of MEK and mTOR on downstream signaling and tumor growth in pancreatic cancer xenograft models."  Cancer Biol. Ther. 8:  1893-1901 (2009).
When fractionated tumor-localized radiotherapy (5 x 2 Gy) was combined with selumetinib treatment, the growth delay of Calu-6 lung and colorectal tumor xenografts was enhanced significantly when compared with either treatment alone.  Shannon, A.M., et al.  "The mitogen-activated protein/extracellular signal-regulated kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) enhances the radiation responsiveness of lung and colorectal tumor xenografts."  Clin. Cancer Res. 15:  6619-6629 (2009).
The levels of phosphorylated AKT were significantly higher in resistant lung cancer cells than in the sensitive cells.  Phosphorylated AKT can be used as a molecular biomarker to predict lung cancer response to MEK inhibitors.  Meng, J., et al.  "High level of AKT activity is associated with resistance to MEK inhibitor AZD6244 (ARRY-142886)."  Cancer Biol. Ther. 8:  2073-2080 (2009).
Selumetinib was cytostatic and inhibited the growth of melanoma cells in vitro.  In vivo, selumetinib treatment decreased phospho-ERK in the 1205Lu melanoma tumors and significantly suppressed tumor growth in severe combined immunodeficient mice.  But selumetinib monotherapy was largely only cytostatic because the original tumors remained viable.  Combination treatment of selumetinib with docetaxel caused tumor regression.  Haass, N.K., et al.  "The mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor AZD6244 (ARRY-142886) induces growth arrest in melanoma cells and tumor regression when combined with docetaxel."  Clin. Cancer Res. 14:  230-239 (2008).
Selumetinib inhibited the growth of a spectrum of thyroid cancer cells by inhibiting the MEK-ERK pathway.  However, the inhibitory effect was cytostatic in papillary thyroid cancer and anaplastic thyroid cancer cells bearing a BRAF mutation.  Selumetinib may have less inhibitory impact on thyroid cancer cells lacking this mutation.  Ball, D.W., et al.  "Selective growth inhibition in BRAF mutant thyroid cancer by the mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244."  J. Clin. Endocrinol. Metab. 92:  4712-4718 (2007).
Selumetinib induced myeloma-cell cytotoxicity and inhibited osteoclastogenesis, possibly by inhibiting MEK.  Tai Y.T., et al.  "Targeting MEK induces myeloma-cell cytotoxicity and inhibits osteoclastogenesis."  Blood 110:  1656-1663 (2007).
Related CAS numbers:  943332-08-9 for the selumetinib sulfate.
Another CAS number previously assigned to Selumetinib, Free Base, namely 865610-79-3, has been deleted by CAS and is no longer in use.
Storage:  Store at or below -20 ºC.  Solubility:  Soluble in DMSO at 200 mg/mL; soluble in ethanol at 2.5 mg/mL with warming; very poorly soluble in water; maximum solubility in plain water is estimated to be about 25-50 µM; buffers, serum, or other additives may increase or decrease the aqueous solubility.  Disposal:  A
 

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