Trametinib (DMSO solvate) (GSK-1120212 (DMSO solvate);JTP-74057 (DMSO solvate)) is an orally active MEK inhibitor that inhibits MEK1 and MEK2 with IC₅₀s of about 2 nM. Trametinib (DMSO solvate) activates autophagy and induces apoptosis^[1][2].

In BRAF mutant SK-MEL-28 cells and KRAS mutant HCT116 cells, Trametinib (GSK1120212;JTP-74057) DMSO solvate causes dose-dependent inhibition of ERK1/2 phosphorylation as well as dose-dependent growth inhibition. In both SK-MEL-28 and HCT116 cells, Trametinib DMSO solvate inhibits 50% p-ERK1/2 at nearly equivalent concentrations (0.8 and 1.8 nM, respectively). However, as the slopes of the curves reflect, in SK-MEL-28 cells, 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 concentrations Trametinib DMSO solvate that produces near complete ERK1/2 inhibition (85 and 90%, respectively)^[2].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

Trametinib (GSK1120212;JTP-74057) DMSO solvate is evaluated in vivo in an A549 (KRAS mutant cell line) xenograft model, orally dosing daily for 21 days (qd×21). In this study, near complete tumor growth inhibition is observed at 5.0 and 2.5 mg/kg [92 and 87% tumor growth inhibition (TGI), respectively] and to a lesser degree at 0.5 and 0.1 mg/kg (62 and 58% TGI). Although 5 mg/kg is the maximally tolerated dose (MTD) in this study, 3 mg/kg is the typically observed MTD. Dose-dependent antitumor activity with Trametinib DMSO solvate treatment has been similarly reported for several other KRAS and BRAF mutant tumor models^[2].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

693.53

C₂₈H₂₉FIN₅O₅S

1187431-43-1

曲美替尼二甲亚砜

Room temperature in continental US; may vary elsewhere.

DMSO : 69 mg/mL (99.49 mM; Need ultrasonic)

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；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。
储备液的保存方式和期限：-80°C, 6 months; -20°C, 1 month。-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。

请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照 In Vitro 方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；体内实验的工作液，建议您现用现配，当天使用； 以下溶剂前显示的百
分比是指该溶剂在您配制终溶液中的体积占比；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的方式助溶

• 1.

  请依序添加每种溶剂： 10% DMSO    40% PEG300    5% Tween-80    45% saline

  Solubility: ≥ 2.5 mg/mL (3.60 mM); Clear solution

  此方案可获得 ≥ 2.5 mg/mL (3.60 mM，饱和度未知) 的澄清溶液。

  以 1 mL 工作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀；向上述体系中加入50 μL Tween-80，混合均匀；然后继续加入 450 μL生理盐水定容至 1 mL。

  将 0.9 g 氯化钠，完全溶解于 100 mL ddH₂O 中，得到澄清透明的生理盐水溶液

• 2.

  请依序添加每种溶剂： 10% DMSO    90% (20% SBE-β-CD in saline)

  Solubility: 2.5 mg/mL (3.60 mM); Suspended solution; Need ultrasonic

  此方案可获得 2.5 mg/mL (3.60 mM) 的均匀悬浊液，悬浊液可用于口服和腹腔注射。

  以 1 mL 工作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 900 μL 20% 的 SBE-β-CD 生理盐水水溶液中，混合均匀。

  将 2 g 磺丁基醚 β-环糊精加入 5 mL 生理盐水中，再用生理盐水定容至 10 mL，完全溶解，澄清透明
• 3.

  请依序添加每种溶剂： 10% DMSO    90% corn oil

  Solubility: ≥ 2.5 mg/mL (3.60 mM); Clear solution

  此方案可获得 ≥ 2.5 mg/mL (3.60 mM，饱和度未知) 的澄清溶液，此方案不适用于实验周期在半个月以上的实验。

  以 1 mL 工作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 900 μL玉米油中，混合均匀。

• [1]. Yamaguchi T, et al. Suppressive effect of an orally active MEK1/2 inhibitor in two different animal models for rheumatoid arthritis: a comparison with HWA486. 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 Chem Lett. 2011 Feb 28;2(4):320-4.

SK-MEL-28, and HCT116 cell lines are plated in triplicate 96 well microtitre plates at 5000 cells per well in culture media. Trametinib dissolved in DMSO or negative control (0.1% DMSO) are added the following day and one plate is harvested with 50 μL of CellTiter-Glo for a time 0 (T=0) measurement. Remaining duplicate cell plates are typically incubated for 72 h. Cells are then lysed with 50 μL CellTiter-Glo, and chemiluminescent signal is read on the Wallac EnVision 2100 plate reader. For measurement of cellular ERK1/2 phosphorylation, cells are seeded and treated with Trametinib, and lysed after 72 h in Tris lysis buffer 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-fitting tool. For comparison of the growth assay curve and pERK1/2 assay curve, data are background subtracted and normalized to the vehicle treatment control^[2].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

Mice^[2]
A549 (human non-small cell lung carcinoma) model is established from cells grown in tissue culture and harvested aseptically using a trypsin digest. Female athymic mice (strain nu/nu) are injected subcutaneously with between 5×10⁶ and 10⁷ cells in 50% martigel. Tumors are allowed to establish for one to four weeks before use. Trametinib is administered orally at the indicated doses in 0.2 mL/20 g by weight. Tumors are measured twice weekly using Vernier calipers. Antitumor activity is defined as tumor growth inhibition representing the % volume differential in tumor growth between the treated and control tumors at the time vehicle tumors exceeded a volume of 1000 mm³.

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

• [1]. Yamaguchi T, et al. Suppressive effect of an orally active MEK1/2 inhibitor in two different animal models for rheumatoid arthritis: a comparison with HWA486. 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 Chem Lett. 2011 Feb 28;2(4):320-4.