Selumetinib (AZD6244) is a potent, highly selective MEK inhibitor with IC50 of 14 nM for MEK1 and Kd value of 530 nM for MEK2. It also inhibits ERK1/2 phosphorylation with IC50 of 10 nM, no inhibition to p38α, MKK6, EGFR, ErbB2, ERK2, B-Raf, etc. Phase 3.
Left: BRAFV600E A375 cells expressing pLKO or shMED12 vectors were cultured in the absence or presence of 2.5 μM PLX4032 or 0.5 μM AZD6244. The cells were fixed, stained, and photographed after 10 (untreated) or 28 days (treated). Right: A375 cells expressing pLKO or shMED12 vectors were grown in the absence or presence of 1 μM PLX4032 or 0.5 μM AZD6244 for 6 hr.
Cell, 2012, 151(5): 937–950. Selumetinib (AZD6244) purchased from Selleck.
A,ERK phosphorylation in A375 expressing indicated ORFs following treatment with DMSO or 1 μM of PLX4720, RAF265, CI-1040 or AZD6244. B,ERK phosphorylation in A375 expressing indicated ORFs following treatment with DMSO, PLX4720 (1 μM) or PLX4720 in combination with CI-1040 or AZD6244 (all 1 μM).
Nature 2010 468, 968-972. Selumetinib (AZD6244) purchased from Selleck.
Survival curves for isogenic cell line pairs and melanoma cultures treated with the indicated AZD6244 concentration for 72 h (relative to DMSO treated controls; mean6s.e.m., n55). PLX4032 resistant cells were grown with PLX4032. Dashed line, 50% cell killing.
Nature 2010 468, 973-977. Selumetinib (AZD6244) purchased from Selleck.
a-c, Inhibitors of BRAFV600E (PLX4032) and MEK1/2 (PD98059 or AZD6244) increase PGC1α and ID2 expression (a, b) and repress integrin expression and signalling (b, c). Cells were treated with indicated concentration of inhibitors for 6 h (a, b) or 24 h (c). d, e, PLX4032 increases the interaction between ID2 and TCF4 (d) and decreases the occupancy of TCF4 at the promoters of integrin genes (e). f–g, PGC1α and ID2 are partially required for PLX4032-mediated inhibition of invasion and metastasis. For in vitro assays (f), A375 cells were incubated with 1 μM PLX4032 for 10 h. Images represent one picture captured per membrane with the scale bar representing 200 μm. Values in a, b, e and f represent mean±s.d. of independent biological triplicates; *P<0.05 and **P<0.01 by Student's t-test in a, b, e, f.
Nature, 2016, 537(7620):422-428.. Selumetinib (AZD6244) purchased from Selleck.
Parental murine KRasG12V;p53-/- lung cancer cells or the same cell lines stably expressing exogenous KRASWT or KRASD154Q were injected intravenously into nude mice. After one week, animals were treated with selumetinib (50 mg/kg daily) and sacrificed at the indicated time points. Lungs were lysed and analyzed by western blot with the indicated antibodies.
Cell, 2018, 172(4):857-868. Selumetinib (AZD6244) purchased from Selleck.
Ex vivo and functional characterization of MEK1(P124L). (A) AZD6244-mediated growth inhibition ex vivo of treatment-naïve BRAFV600E melanoma cells (black and blue) or cells cultured from an AZD6244-resistant metastatic focus (red). (B) ERK phosphorylation (p-ERK) andMEKphosphorylation (p-MEK) are shown following treatment with increasing concentrations of AZD6244 in treatment-naïve or AZD6244-resistant melanoma cells cultured ex vivo. The tubulin loading control (-tubulin) is also shown. (C) AZD6244 growth inhibition curves of parental A375 (solid black), A375 cells expressing MEK-DD (grey), wild-type MEK1 (hatched black), or MEK1(P124L) (red) are shown. In each instance n6 anderrorstandard deviation. (D) p-ERK and p-MEK are shown following treatment with increasing AZD6244 concentrations in the cell lines described in C, Above. The -tubulin control is also shown.
Proc Natl Acad Sci USA 2009 106, 20411-20416. Selumetinib (AZD6244) purchased from Selleck.
AZD6244 enhanced FOXO3a expression and induced suppression of cancer cell proliferation. A, tumor volume of the HCT116 xenografts treated with Placebo or AZD6244 was measured for 21 d. The tumor sections of four individual DMSO or AZD6244-treated HCT116 xenografts were subjected to immunohistochemistry with a FOXO3a antibody. Relative percentages of nuclear FOXO3a expression of individual xenograft tumors from B were analyzed and the mean values of FOXO3a expression in Placebo or AZD6244-treated group were indicated as bars.
Cancer Res 2010 70, 4709-4718. Selumetinib (AZD6244) purchased from Selleck.
lysates from various cancer cell lines: breast cancer (MDA-MB-435), colon cancer (HCT116, SW620, and HT29), and melanoma (WM793) treated with DMSO or AZD6244 (10 μmol/L) for 4 h were subjected to immunoblotting with the indicated antibodies.
Cancer Res 2010 70, 4709-4718. Selumetinib (AZD6244) purchased from Selleck.
A and B, clonogenic assays in 2 melanoma cell lines (YUVON and YUSIK) treated with NVPBEZ235 (BEZ) and AZD6244 (AZD) alone and in combination. Combinations were more effective in inhibiting colony formation at lower concentrations than either drug alone.
Clin Cancer Res 2010 16, 6029-6039. Selumetinib (AZD6244) purchased from Selleck.
Concentration equilibrium transport assays (CETAs) for selumetinib using parental and (murine) Mdr1a or (human) MDR1 overexpressing LLC cells. Zosuquidar (5 μM) was used to specifically inhibit P-gp mediated transport. Data are means ± SD; n = 6; ** p < 0.01, *** p < 0.001.
Int J Cancer, 2018, 142(2):381-391. Selumetinib (AZD6244) purchased from Selleck.
INA-6 MM cells were treated with AS703026 or AZD6244 for 2 d, followed by [3H]thymidine uptake assay. PBMCs isolated from normal donors (n = 3) were incubated with M-CSF and RANKL, in the presence or absence of AS703026 or AZD6244 for 14 d. The TRAP assay was performed to measure the formation of multinuclear osteoclast cells (OC).
Br J Haematol 2010 149, 537–549. Selumetinib (AZD6244) purchased from Selleck.
B-RafV600E mutated melanoma line,A375, was treated with different doses of AZD6244 for 1hour or 24 hours.Cell lysates were analyzed by Western Blotting to determine the levels of phosphorylated ERK1/2(Perk1/2)
Dr. Jong-In Park of Medical College of Wisconsin. Selumetinib (AZD6244) purchased from Selleck.
|製品説明||Selumetinib (AZD6244) is a potent, highly selective MEK inhibitor with IC50 of 14 nM for MEK1 and Kd value of 530 nM for MEK2. It also inhibits ERK1/2 phosphorylation with IC50 of 10 nM, no inhibition to p38α, MKK6, EGFR, ErbB2, ERK2, B-Raf, etc. Phase 3.|
|特性||First MEK inhibitor being tested in Phase II clinical trials.|
AZD6244 is not competitive with ATP and inactivates the ERK1/2 phosphorylation with IC50 concentrations below 40 nM. AZD6244 also inhibits the growth of primary HCC cells through inhibition of ERK1/2 and p90RSK phosphorylation, accompanied with elevation of the cleavage of caspase-3 and caspase-7, and cleaved poly(ADP)ribose polymerase. AZD6244 has little effects on the p38, c-Jun-NH2-kinase, phosphatidylinositol 3-kinase, and MEK5/ERK5 pathways.  AZD6244 is sensitive to Raf mutations in breast cancer cell lines and Ras mutations in NSCLC cell lines. 
|体内試験||AZD6244 significantly inhibits phosphorylation of ERK1/2 in 2-1318, 5-1318, 26-1004 and 4-1318 xenografts and induces apoptosis in primary 2-1318 cells by activating the caspase pathway.  AZD6244 could inhibit the tumor growth in HT-29 xenograft, which is a colorectal tumor model carrying a B-Raf mutation, at a dose of 100 mg/kg and the tumor growth inhibition of AZD6244 is better than it of Gemcitabine.  Otherwise AZD6244 could inhibit HCC xenografts tumor growth, which associated with increased apoptosis and down-regulation of cell cycle regulators, including cyclin D1, Cdc-2, CDK2 and 4, cyclin B1, and c-Myc. |
Assay of MEK Kinase Activity:Anti-MEK1 antibody is used to immunoprecipitate MEK1 molecules. MEK kinase activity is measured as the ability of immuno-isolated MEK1 to activate recombinant ERK1 in a coupled assay using MBP as the end point of the assay. Phosphorylated MBP is resolved on a 14% SDS-PAGE gel and vacuum-dried before exposure to X-ray film.
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-  Yeh TC, et al, Clin Cancer Res, 2007, 13 (5), 1576-1583.
-  Huynh H, et al, Mol Cancer Ther, 2007, 6 (9), 2468-2476.
-  Davies BR, et al. Mol Cancer Ther, 2007, 6(8), 2209-2219.
-  Morelli MP, et al. Clin Cancer Res, 2012, 18(4), 1051-1062.
-  Yuen JS, et al. Int J Oncol, 2012, 41(2), 712-720.
-  Leboeuf R, et al. J Clin Endocrinol Metab, 2008, 93(6), 2194-2201.
-  Emery CM,, et al. Proc Natl Acad Sci U S A, 2009, 106(48), 20411-20416.
-  Friday BB, et al. Cancer Res, 2008, 68(15), 6145-6153.
-  Huynh H, et al. J Hepatol, 2010, 52(1), 79-87.
-  Diep CH, et al. Clin Cancer Res, 2011, 17(9), 2744-2756.
-  Davis MI, et al. Nat Biotechnol. 2011, 29(11):1046-51.
|体外||DMSO||91 mg/mL (198.82 mM) warming|
4% DMSO+30% PEG 300+5% Tween 80+ddH2O
質量 (g) = 濃度 (mol/L) x 体積 (L) x 分子量 (g/mol)
開始濃度 x 開始体積 = 最終濃度 x 最終体積
この方程式は、一般に略語を使われます：C1V1 = C2V2 ( 入力 出力 )
チップス: 化学式は大文字と小文字の区別ができます。C10H16N2O2 c10h16n2o2
|NCT Number||Recruitment||Conditions||Sponsor/Collaborators||Start Date||Phases|
|NCT01287130||Completed||Colonic Neoplasms|Cancer of the Colon|Colon Cancer|Colon Neoplasms|Colonic Cancer||National Cancer Institute (NCI)|National Institutes of Health Clinical Center (CC)||January 7, 2011||Phase 1|
|NCT01134601||Terminated||Non-Metastatic Adenocarcinoma of the Rectum||National Cancer Institute (NCI)|National Institutes of Health Clinical Center (CC)||May 24, 2010||Phase 1|
|NCT01306045||Recruiting||Carcinoma, Non-Small-Cell Lung|Carcinoma, Small Cell Lung|Carcinoma, Thymic||National Cancer Institute (NCI)|National Institutes of Health Clinical Center (CC)||January 21, 2011||Phase 2|
|NCT03040986||Not yet recruiting||KRAS NP_004976.2:p.G12R|Stage II Pancreatic Cancer|Stage IIA Pancreatic Cancer|Stage IIB Pancreatic Cancer|Stage III Pancreatic Cancer|Stage IV Pancreatic Cancer||National Cancer Institute (NCI)||July 2017||Phase 2|
|NCT03004105||Not yet recruiting||Malignant Neoplasm of Respiratory and Intrathoracic Organ Carcinoma|Advanced Lung Cancer|Recurrent Nonsmall Cell Lung Cancer||M.D. Anderson Cancer Center|AstraZeneca|MedImmune LLC||April 2017||Phase 2|
|NCT02839720||Not yet recruiting||Appearance Distress|Bothered by Itching Skin|Cafe Au Lait Spot|Cutaneous Neurofibroma|Disfigurement|Dysplasia|Lisch Nodule|Neurofibromatosis Type 1|NF1 Gene Mutation|Optic Nerve Glioma||National Cancer Institute (NCI)||January 2017||--|
How about the solubility of S1008? How to prepare for the solution if I need to do the in vivo experiments?
S1008 AZD6244 in vehicle 5% DMSO+30% PEG 300+ddH2O will be a suspension for oral administration. If you want a clear solution for injection, you can dissolve it in 4% DMSO+30% PEG 300+5% Tween 80+ddH2O.