1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemETrametinib DMSO solvateCat. No.: HY-10999ACAS No.: 1187431-43-1Synonyms: GSK-1120212 (DMSO solvate); JTP-74057 (DMSO solvate)分式: CHFINOS分量: 693.53作靶點: MEK作通路: MAPK/ERK Pathway儲存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 m

2、onths-20C 1 month溶解性數(shù)據(jù)體外實驗 DMSO : 69 mg/mL (99.49 mM; Need ultrasonic)H2O : 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (3.60 mM); Clear solution2. 請依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.5 mg/mL (3.60 mM); Suspended solution; Need ultrasonic1/3 Master of Small Molecul

3、es 您邊的抑制劑師www.MedChemE3. 請依序添加每種溶劑： 10% DMSO 90% corn oilSolubility: 2.5 mg/mL (3.60 mM); Clear solutionBIOLOGICAL ACTIVITY物活性 Trametinib DMSO solvate種有效的 MEK 抑制劑，特異性抑制 MEK1/2，IC50 約為 2 nM。IC50 & Target MEK1 MEK22 nM (IC50) 2 nM (IC50)體外研究 In BRAF mutant SK-MEL-28 cells and KRAS mutant HCT116 cells,

4、 Trametinib (GSK1120212) DMSO solvatecauses dose-dependent inhibition of ERK1/2 phosphorylation as well as dose-dependent growth inhibition. Inboth SK-MEL-28 and HCT116 cells, Trametinib DMSO solvate inhibits 50% p-ERK1/2 at nearly equivalentconcentrations (0.8 and 1.8 nM, respectively). However, as

5、 the slopes of the curves reflect, in SK-MEL-28cells, Trametinib DMSO solvate inhibits 90% p-ERK1/2 at a lower concentration (3.4 nM) than in HCT116(33.3 nM). Furthermore, in both cell lines, 50% growth inhibition is only achieved at concentrationsTrametinib DMSO solvate that produces near complete

6、ERK1/2 inhibition (85 and 90%, respectively) 2.體內(nèi)研究 Trametinib (GSK1120212) DMSO solvate is evaluated in vivo in an A549 (KRAS mutant cell line) xenograftmodel, orally dosing daily for 21 days (qd21). In this study, near complete tumor growth inhibition isobserved at 5.0 and 2.5 mg/kg 92 and 87% tum

7、or growth inhibition (TGI), respectively and to a lesserdegree at 0.5 and 0.1 mg/kg (62 and 58% TGI). Although 5 mg/kg is the maximally tolerated dose (MTD) inthis study, 3 mg/kg is the typically observed MTD. Dose-dependent antitumor activity with Trametinib DMSOsolvate treatment has been similarly

8、 reported for several other KRAS and BRAF mutant tumor models 2.PROTOCOLCell Assay 2 SK-MEL-28, and HCT116 cell lines are plated in triplicate 96 well microtitre plates at 5000 cells per well inculture media. Trametinib dissolved in DMSO or negative control (0.1% DMSO) are added the following dayand

9、 one plate is harvested with 50 L of CellTiter-Glo for a time 0 (T=0) measurement. Remaining duplicatecell plates are typically incubated for 72 h. Cells are then lysed with 50 L CellTiter-Glo, andchemiluminescent signal is read on the Wallac EnVision 2100 plate reader. For measurement of cellularER

10、K1/2 phosphorylation, cells are seeded and treated with Trametinib, and lysed after 72 h in Tris lysisbuffer supplemented with phosphatase and protease inhibitors. All samples are analyzed with a phospho-ERK1/2 ELISA. Plates are read on MSD.SI6000 and curves are analyzed using the XLfit curve-fittin

11、g tool.For comparison of the growth assay curve and pERK1/2 assay curve, data are background subtracted andnormalized to the vehicle treatment control 2.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Mice 2Administration 2 A549 (human non-small

12、cell lung carcinoma) model is established from cells grown in tissue culture andharvested aseptically using a trypsin digest. Female athymic mice (strain nu/nu) are injected subcutaneously2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEwith between 5106 and 107 cells in 50% martigel. Tumors are all

13、owed to establish for one to four weeksbefore use. Trametinib is administered orally at the indicated doses in 0.2 mL/20 g by weight. Tumors aremeasured twice weekly using Vernier calipers. Antitumor activity is defined as tumor growth inhibitionrepresenting the % volume differential in tumor growth

14、 between the treated and control tumors at the timevehicle tumors exceeded a volume of 1000 mm3.MCE has not independently confirmed the accuracy of these methods. They are for reference only. Cell. 2018 Aug 9;174(4):843-855.e19. Cancer Discov. 2018 Mar;8(3):354-369. Cancer Discov. 2015 Sep;5(9):960-

15、71. Cancer Discov. 2012 Oct;2(10):934-47. Cell Metab. 2019 Jan 8;29(1):141-155.e9.See more customer validations on HYPERLINK / www.MedChemEREFERENCES1. Yamaguchi T, et al. Suppressive effect of an orally active MEK1/2 inhibitor in two different animal models for rheumatoid arthritis: acomparison with leflunomide. Inflamm Res, 2012, 61(5), 445-454.2. Abe H, et al. Discovery of a Highly Potent and Selective MEK Inhibitor: GSK1120212 (JTP-74057 DMSO Solvate). ACS Med