司美替尼作用机制- Medchemexpress- MCE中国 - 图文

Product Data?SheetSelumetinibCat. No.:CAS No.:分?式:分?量:作?靶点:作?通路:储存?式:HY-50706606143-52-6C??H??BrClFN?O?457.68MEK; ApoptosisMAPK/ERK Pathway; ApoptosisPowderIn solvent-20°C4°C-80°C-20°C3 years2 years6 months1 monthInhibitors?Agonists?Screening Libraries溶解性数据体外实验DMSO : 20.83 mg/mL (45.51 mM; Need ultrasonic)Mass1 mg5 mg10 mgSolventConcentration制备储备液1 mM5 mM10 mM2.1849 mL0.4370 mL0.2185 mL10.9247 mL2.1849 mL1.0925 mL21.8493 mL4.3699 mL2.1849 mL请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；?旦配成溶液，请分装保存，避免反复冻融造成的产品失效。储备液的保存?式和期限：-80°C, 6 months; -20°C, 1 month。-80°C 储存时，请在 6 个?内使?，-20°C 储存时，请在 1 个?内使?。体内实验请根据您的实验动物和给药?式选择适当的溶解?案。以下溶解?案都请先按照 In Vitro ?式配制澄清的储备液，再依次添加助溶剂： 为保证实验结果的可靠性，澄清的储备液可以根据储存条件，适当保存；体内实验的?作液，建议您现?现配，当天使?； 以下溶剂前显?的百分?是指该溶剂在您配制终溶液中的体积占?；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的?式助溶1. 请依序添加每种溶剂：?10% DMSO ?? 40% PEG300 ?? 5% Tween-80 ?? 45% salineSolubility: ≥ 2.08 mg/mL (4.54 mM); Clear solution此?案可获得 ≥ 2.08 mg/mL (4.54 mM，饱和度未知) 的澄清溶液。 以 1 mL ?作液为例，取 100 μL 20.8 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀；向上述体系中加? 50 μL Tween-80，混合均匀；然后继续加? 450 μL ?理盐?定容? 1 mL。2. 请依序添加每种溶剂：?10% DMSO ?? 90% (20% SBE-β-CD in saline)Solubility: ≥ 2.08 mg/mL (4.54 mM); Clear solution此?案可获得 ≥ 2.08 mg/mL (4.54 mM，饱和度未知) 的澄清溶液。 Page 1 of 2 www.MedChemExpress.cn

以 1 mL ?作液为例，取 100 μL 20.8 mg/mL 的澄清 DMSO 储备液加到 900 μL 20% 的 SBE-β-CD ?理盐??溶液中，混合均匀。3. 请依序添加每种溶剂：?10% DMSO ?? 90% corn oilSolubility: ≥ 2.08 mg/mL (4.54 mM); Clear solution此?案可获得 ≥ 2.08 mg/mL (4.54 mM，饱和度未知) 的澄清溶液，此?案不适?于实验周期在半个?以上的实验。 以 1 mL ?作液为例，取 100 μL 20.8 mg/mL 的澄清 DMSO 储备液加到 900 μL ??油中，混合均匀。BIOLOGICAL ACTIVITY?物活性Selumetinib (AZD6244) 是?种?效选择性的，? ATP 竞争性的 MEK1/2 抑制剂， 抑制 MEK1 的 IC50 为14 nM。Selumetinib (AZD6244) 抑制 MEK1/2 磷酸化?平。IC?? & TargetMEK12 nM (IC50)体外研究MEK114 nM (IC50)MEK2?Selumetinib (AZD6244) causes a time- and dose-dependent reduction in DNA synthesis and cell viability in primary, induces growth arrest and apoptosis associated with the inactivation of ERK in primary 2-1318 cells[1]. Selumetinib (AZD6244) (1μM) shows anti-proliferative effects through G0/G1 arrest on H-441, H-1437 cells[2]. Selumetinib (AZD6244) results in the growth inhibition of several cell lines containing B-Raf and Ras mutations but has no effect on a normal fibroblast cell line[3].体内研究Selumetinib (AZD6244, 50 and 100 mg/kg, p.o.) decreases the growth rate of 4-1318 xenografts in a dose-dependent manner; AZD6244 when given at the dose of 50 mg/kg also significantly suppresses the growth of the 5-1318, 2-1318, 26-1004, and 29-1104 xenografts[1]. Selumetinib (ARRY-142886, 10, 25, 50, or 100 mg/kg, p.o.) is capable of inhibiting both ERK1/2 phosphorylation and growth of HT-29 xenograft tumors in nude mice. Tumor regressions are also seen in a BxPC3 xenograft model[3].PROTOCOLKinase Assay [3]The activity of MEK1 is assessed by measuring the incorporation of [γ-33P]phosphate from [γ-33P]ATP onto ERK2. The assay is carried out in a 96-well polypropylene plate with an incubation mixture (100 μL) composed of 25 mM HEPES (pH 7.4), 10 mM MgCl2, 5 mM β-glycerolphosphate, 100 μM sodium orthovanadate, 5 mM DTT, 5 nM MEK1, 1 μM ERK2, and 0 to 80 nM selumetinib (final concentration of 1% DMSO). The reactions are initiated by the addition of 10 μM ATP (with 0.5 μC k[γ-33P]ATP/well) and incubated at room temperature for 45 min. An equal volume of 25% trichloracetic acid is added to stop the reaction and precipitate the proteins. Precipitated proteins are trapped onto glass fiber B filter plates, excess labeled ATP is washed off with 0.5% phosphoric acid, and radioactivity is counted in a liquid scintillation counter. ATP dependence is determined by varying the amount of ATP in the reaction mixture.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Cell Assay [1]Primary HCC cells are plated at a density of 2.0×104?per well in growth medium. After 48 h in growth medium, the cell monolayer is rinsed twice with MEM. Cells are treated with various concentrations of Selumetinib (AZD6244, 0, 0.5, 1.0, 2.0, 3.0, and 4.0 μM) for 24 or 48 h. Cell viability is determined by the MTT assay. Cell proliferation is assayed using a bromodeoxyuridine kit as described by the manufacturer. Experiments are repeated at least thrice, and the data are expressed as mean±SE.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Page 2 of 3

To investigate the effects of Selumetinib (AZD6244) on HCC xenografts, AZD6244 is suspended in water at an www.MedChemExpress.cn

Administration [1]

appropriate concentration. Mice bearing HCC xenografts are p.o. given, twice a day, with either 100 μL of water (n=12) or 50 mg (n=12) or 100 mg (n=12) of AZD6244 per kilogram of body weight for 21 days, starting from day 7 after tumor implantation. Growth of established tumor xenografts is monitored at least twice weekly by Vernier caliper measurement of the length (a) and width (b) of the tumor. Tumor volume is calculated as (a × b2)/2. Animals are sacrificed 3 h after the last dose of ADZ6244, and body and tumor weights are recorded, with the tumors harvested for analysis.

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

客户使?本产品发表的科研?献

????Cancer Cell. 2020 Mar 16;37(3):387-402.e7.????Genome Med. 2016 Oct 31;8(1):116.????Neuro Oncol. 2019 Mar 18;21(4):486-497.????Mol Syst Biol. 2015 Mar 26;11(3):797.

????Clin Cancer Res.?2020 Jan 14. pii: clincanres.2884.2019.See more customer validations on www.MedChemExpress.cnREFERENCES

[1].?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 Therapy, 2007, 6 (1), 138-146

[2].?Garon EB, et al. Identification of common predictive markers of in vitro response to the Mek inhibitor selumetinib (AZD6244; ARRY-142886) in human breast cancer and non-small cell lung cancer cell lines. Mol Cancer Thera, 2010, 9 (7), 1985-1994.

[3].?Yeh TC, et al. Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clin Cancer Res, 2007, 13 (5), 1576-1583.

[4].?Sebolt-Leopold JS, et al. Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer. 2004 Dec;4(12):937-47.

[5].?Dela Cruz FS, et al. A case study of an integrative genomic and experimental therapeutic approach for rare tumors: identification of vulnerabilities in a pediatric poorly differentiated carcinoma. Genome Med. 2016 Oct 31;8(1):116.

[6].?Weisberg E, et al. Upregulation of IGF1R by mutant RAS in leukemia and potentiation of RAS signaling inhibitors by small-molecule inhibition of IGF1R. Clin Cancer Res. 2014 Nov 1;20(21):5483-95.

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