Mirdametinib (PD0325901)

製品コードS1036 バッチS103612

印刷

化学情報

Chemical Structure Synonyms N/A Storage
(From the date of receipt)		 3 years -20°C powder
1 years -80°C in solvent
化学式

C16H14F3IN2O4
分子量 482.19 CAS No. 391210-10-9
Solubility (25°C)* 体外 DMSO 96 mg/mL (199.09 mM)
Ethanol 96 mg/mL (199.09 mM)
Water Insoluble
体内 （毎回新しく調製した物を用意してください）
Homogeneous suspension
CMC-NA
≥5mg/ml Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Clear solution
5%DMSO 40%PEG300 5%Tween80 50%ddH2O

この製剤はselleckのラボで検証済みです。上記の溶解方法がご要望を満たさない場合、selleckの営業担当までお問い合わせ頂ければ、個別の試験を行います。

 5.000mg/ml (10.37mM) Taking the 1 mL working solution as an example, add 50 μL of 100 mg/ml clarified DMSO stock solution to 400 μL of PEG300, mix evenly to clarify it; add 50 μL of Tween80 to the above system, mix evenly to make it clear; then continue to add 500 μL of ddH2O to adjust the volume to 1 mL. The mixed solution should be used immediately for optimal results. 
Clear solution
5% DMSO 95% Corn oil

この製剤はselleckのラボで検証済みです。上記の溶解方法がご要望を満たさない場合、selleckの営業担当までお問い合わせ頂ければ、個別の試験を行います。

 0.400mg/ml (0.83mM) Taking the 1 mL working solution as an example, add 50 μL of 8 mg/ml clear DMSO stock solution to 950 μL of corn oil and mix evenly. The mixed solution should be used immediately for optimal results. 
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

溶剤液（一定の濃度）を調合する

生物活性

製品説明 ミルダメチニブ (Mirdametinib (PD0325901)) は選択的非 ATP 競合性 MEK 阻害剤です。Cell-free assay における IC50 は0.33 nM で、ERK1 および ERK2 のリン酸化に対して CI-1040 よりも約 500 倍の活性を有しています。臨床第2相試験中
in vitro Mirdametinib (PD0325901) shows higher permeability than CI-1040, another MEK inhibitor, and should be able to achieve higher systemic exposures. [1] This compound is exquisitely specific and highly potent against purified MEK, revealing a Kiapp of 1 nM against activated MEK1 and MEK2. [2] It is roughly 500-fold more potent than CI-1040 with respect to its cellular effects on phosphorylation of ERK1 and ERK2, displaying subnanomolar activity. [2] It prevents the growth of melanoma cell lines and inhibits the growth of TPC-1 cells and K2 cells with GI50 of 11 nM and 6.3 nM, respectively. [3] It significantly prevents the growth of PTC cells harboring a BRAF mutation at very low concentration (10 nM) and only moderately increases the growth of the PTC cells carrying the RET/PTC1 rearrangement at the same concentration. This compound effectively inhibits the phosphorylation of ERK1/2 in multiple PTC cell lines. [3]
in vivo The improved potency of Mirdametinib (PD0325901) relative to CI-1040 is evident. A single oral dose of this compound (25 mg/kg) inhibits phosphorylation of ERK by more than 50% at 24 hours post-dosing. In contrast, CI-1040 at a much higher dose (150 mg/kg) only inhibits pERK levels for roughly 8 hours, returning to control levels by 24 hours after treatment. [2] Therefore, the dose required to produce a 70% incidence of complete tumor responses (C26 model) is 25 mg/kg/day versus 900 mg/kg/day for it and CI-1040, respectively. Anticancer activity of PD 0325901 has been demonstrated for a broad spectrum of human tumor xenografts. [2] After 1 week of oral administration of PD0325901 (20–25 mg/kg/day) in mice, no tumor growth is detected in mice inoculated with PTC cells bearing a BRAF mutation. [3] For PTC with the RET/PTC1 rearrangement, the average tumor volume of the orthotopic tumor is decreased by 58% as compared with controls. In conclusion, PTC cells carrying a BRAF mutation are more sensitive to it than are PTC cells carrying the RET/PTC1 rearrangement. [3]

プロトコル(参考用のみ)

キナーゼアッセイ In vitro cascade assay
Incorporation of 32P into myelin basic protein (MBP) is assayed in the presence of a glutathione S-transferase fusion protein containing p44MAP kinase (GST-MAPK) and a glutathione S-transferase protein containing p45MEK (GST-MEK). The assay solution contained 20 mM HEPES, pH 7.4, 10 mM MgCl2, 1 mM MnCl2, 1 mM EGTA, 50 mM [gamma-32P]ATP, 10 mg GST-MEK, 0.5 mg GST-MAPK and 40 mg MBP in a final volume of 100 mL. Reactions are stopped after 20 minutes by addition of trichloroacetic acid and filtered through a GF/C filter mat. 32P retained on the filter mat is determined using a 1205 Betaplate. Mirdametinib (PD0325901) is assessed at various dose ranges in order to determine dose response curves.
細胞アッセイ 細胞株 PTC cells
濃度 0.1 nM- 1 μM
反応時間 48 hours
実験の流れ

PTC cells (1 × 104) are seeded in 24-well plates with 1 mL of medium for 4 days in a 37 °C incubator. Mirdametinib (PD0325901), a MEK inhibitor, is added at varying concentrations to the cells in triplicate on day 0. MTT dissolved in 0.8% NaCl solution at 5 mg/mL is added to each well (0.2 mL) on day 2 to test GI50 or every day for cell growth curves. The cells are incubated at 37 °C for 3 hours with MTT. The liquid is then aspirated from the wells and discarded. Stained cells are dissolved in 0.5 mL of DMSO and their absorption at 570 nm is measured using a Synergy HT multidetection microplate reader. For GI50, cell growth is calculated as 100 × (T − T0)/(C − T0), where T is the optical density of the wells treated with inhibitors after a 48-hour period, T0 is the optical density at time zero, and C is the control optical density with DMSO only.
動物実験 動物モデル Ncr-nu/nu mice bearing PTC cells
投薬量 20-25 mg/kg
投与方法 Oral gavage

参考

  • https://pubmed.ncbi.nlm.nih.gov/18952427/
  • http://aacrmeetingabstracts.org/cgi/content/abstract/2004/1/925
  • https://pubmed.ncbi.nlm.nih.gov/20587665/
  • https://pubmed.ncbi.nlm.nih.gov/22160382/
  • https://pubmed.ncbi.nlm.nih.gov/22399013/
  • https://pubmed.ncbi.nlm.nih.gov/19010912/
  • https://pubmed.ncbi.nlm.nih.gov/18056456/
  • https://pubmed.ncbi.nlm.nih.gov/18952427/

カスタマーフィードバック

Data from [Data independently produced by Nature, 2015, 517(7534), 391-5]

Data from [Data independently produced by Oncogene, 2015, 10.1038/onc.2015.97]

Data from [Data independently produced by J Bone Joint Surg Am, 2015, 96(14), e117]

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長期の保管のために-20°Cの下で製品を保ってください。

人間や獣医の診断であるか治療的な使用のためにでない。

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