Trametinib (GSK1120212) 化学構造
分子量: 615.39

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製品説明

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製品の説明

生物活性

製品説明 Trametinib (GSK1120212)は、非常に特定で有力なMEK1MEK2 阻害剤で、IC50 がそれぞれ 0.92 nM と 1.8 nMです。
ターゲット MEK1 MEK2
IC50 0.92 nM 1.8 nM [1]
In vitro試験 GSK1120212 inhibits the phosphorylation of MBP regardless of the isotype of Raf and MEK, with IC50 ranging from 0.92 nM to 3.4 nM. GSK1120212 demonstrates no inhibition of the kinase activities of c-Raf, B-Raf, ERK1 and ERK2. In addition, GSK1120212 does not show drastic inhibitory activity against the other 98 kinases. GSK1120212 displays potent inhibitory activity against human colorectal cancer cell lines. HT-29 and COLO205 cells, which are known to have a constitutively active B-Raf mutant, are most sensitive to GSK1120212 with IC50 0.48 nM and 0.52 nM, respectively. The cell lines bearing a K-Ras mutation show a wide range of sensitivity to GSK1120212 with IC50 of 2.2-174 nM. In contrast, COLO320 DM cells, bearing the wild-type gene in both B-Raf and K-Ras, are found to be resistant to GSK1120212 even at 10 μM. GSK1120212 treatment for 24 hours induces cell-cycle arrest at the G1 phase in all sensitive cell lines. Consistently, GSK1120212 treatment leads to upregulation of p15INK4b and/or p27KIP1 in most of the colorectal cancer cell lines. GSK1120212 inhibits constitutive ERK phosphorylation in all sensitive cell lines. GSK1120212 induces apoptosis both in HT-29 and COLO205 cells, but that COLO205 cells are more sensitive to GSK1120212 than HT-29 cells in terms of apoptosis induction. [1] GSK1120212 blocks tumor necrosis factor-α and interleukin-6 production from peripheral blood mononuclear cells (PBMCs). [2]
In vivo試験 Oral administration of GSK1120212 at 0.3 mg/kg or 1 mg/kg once daily for 14 days is effective in inhibiting the HT-29 xenograft growth, and 1 mg/kg of GSK1120212 almost completely blocks the tumor increase. The phosphorylation of ERK1/2 is completely inhibited in the established tumor tissues by single oral dose of 1 mg/kg GSK1120212, and both p15INK4b and p27KIP1 protein levels are upregulated after 14 days of treatment with GSK1120212. In the COLO205 xenograft model, tumor regression is observed even at a dose of 0.3 mg/kg. At a dose of 1 mg/kg, a complete regression is obtained in 4 out of 6 mice in which the tumor degenerates to the point that tumor volume is not measurable. [1] Administration of GSK1120212 at 0.1 mg/kg almost completely suppresses adjuvant-induced arthritis (AIA) and type II collagen-induced arthritis (CIA) in Lewis rats or DBA1/J mice, respectively. [2]
臨床試験 A Phase I study to evaluate the effect of repeat oral dosing of GSK1120212 on cardiac repolarization in subjects with solid tumors is currently ongoing.
特集 More potent than PD0325901 or AZD6244.

プロトコル (参考用のみ)

キナーゼアッセイ: [1]

Raf-MEK-ERK cascade kinase assay Non-phosphorylated myelin basic protein (MBP) is coated onto an ELISA plate, and the active form of B-Raf/c-Raf is mixed with unphosphorylated MEK1/MEK2 and ERERK2 in 10 μM ATP and 12.5 mM MgCl2 containing MOPS buffer in the presence of various concentrations of GSK1120212. The phosphorylation of MBP is detected by the anti-phospho-MBP antibody.

細胞アッセイ: [1]

細胞株 HT-29, HCT-15, HCT116, COLO205, LS-174T, SW480, SW620, T84, LoVo and COLO320
濃度 Dissolved in DMSO, final concentrations ~10 μM
反応時間 3 or 4 days
実験の流れ Exponentially growing cells are precultured in 96-well tissue culture plates for 24 hours and then exposed to GSK1120212. Cell growth is determined by an in vitro toxicology assay kit, sulforhodamine B based. For apoptosis assay, both floating and adherent cells are collected and fixed with 70% ethanol. After washing with PBS, the cells are suspended in 100 μg/mL RNase and 25 μg/mL propidium iodide (PI) and incubated at 37 °C for 30 minutes in the dark. The DNA content of each single cell is determined using the flow cytometer Cytomics FC500 or Guava EasyCyte plus.

動物実験: [1]

動物モデル Female BALB/c-nu/nu mice inoculated subcutaneously with HT-29 or COLO205 cells
製剤 Dissolved in 10% Cremophor EL-10% PEG400
投薬量 ~1 mg/kg/day
投与方法 Orally

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

参考

化学情報

Download Trametinib (GSK1120212) SDF
分子量 615.39
化学式

C26H23FIN5O4

CAS No. 871700-17-3
保管 3年-20℃
2年-80℃in solvent
別名 JTP-74057
溶解度 (25°C) * In vitro DMSO 22 mg/mL warming (35.74 mM)
Water <1 mg/mL
Ethanol <1 mg/mL
In vivo 4% DMSO+corn oil 3mg/mL
* <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.
化学名 N-(3-(3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide

文献中の引用 (47)

Frequently Asked Questions

  • Question 1
    Could you help us with the best way to prepare Trametinib for in vivo i.p. injections?

    Answer: S2673 can be dissovled in 4% DMSO/corn oil at 3 mg/ml clearly.

  • Question 2
    How to solve the problem that this product didn't dissolve up to 10mM in DMSO at room temperature?

    Answer: The solution can be heated up to 50 degree to help dissolve. Besides, sonication (with a probe sonicator) also helped greatly.

技術サポート&よくある質問(FAQ)

ストックの作り方、阻害剤の保管する方法、細胞実験や動物実験に注意すべきな点を全部含めており、製品を取扱う時よくあった質問に対して取扱説明書でお答えいたします。

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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