OSI-027 化学構造
分子量: 406.44

品質と確認

カスタマーレビュー(1)

Quality Control & MSDS

製品情報

製品の説明

生物活性

情報 OSI-027は、mTORC1とmTORC2の選択的で強力な二重阻害剤で、IC50 がそれぞれ 22 nM と 65 nMです。
目標

mTORC1

mTORC2

IC50

22 nM [1]

65 nM [1]

In vitro試験 OSI-027 shows the selective and ATP competitive inhibition activities against mTORC1 and mTORC2 with IC50 of 22 nM and 65 nM, respectively. In addition, OSI-027 inhibits mTOR signaling of phospho-4E-BP1 with an IC50 of 1 μM in cell-based assays. [1] OSI-027 exhibits anti-proliferative activities against several acute leukemia cell lines of myeloid/megakaryocytic origin in a dose-dependent manner, including U937, KG-1, KBM-3B, ML-1, HL-60, and MEG-01 cells. [2] A recent study shows that inhibition of mTORC1/2 by OSI-027 effectively suppresses phosphorylation of Akt (S473) and cell proliferation in breast cancer cells. [3]
In vivo試験 In GEO colorectal xenograft, OSI-027 (65 mg/kg) inhibits both mTORC1 and mTORC2 effectors, including 4E-BP1, Akt, and S6 phosphorylation. Furthermore, mTORC1 and mTORC2 inhibition together by OSI-027 potently inhibits tumor growth more than mTORC1 inhibition by rapamycin. [1]
臨床試験 OSI-027 is currently in Phase I clinical trials in patients with Advanced Solid Tumors or Lymphoma.
特集

推薦された実験操作 (公開の文献だけ)

キナーゼアッセイ:

[1]

Biochemical assays mTORC1 and mTORC2 inhibition is assayed using native enzyme complex immunoprecipitated from HeLa lysates at 1 mM ATP. To prepare whole cell lysates from HeLa cells, 25 g cell pellet is lysed in 60 mL of ice-cold buffer A [40 mM HEPES (pH 7.5), 120 mM NaCl, 1 mM EDTA, 10 mM sodium pyrophosphate, 10 mM glycerophosphate, 50 mM NaF, 0.5 mM orthovanadate, and EDTA-free protease inhibitors containing 0.3% CHAPS] for 30 minutes on a magnetic stirrer in a cold room. After clearing of the lysates by centrifugation at 13,000 g for 10 minutes, Protein G-coated 384-well plates are incubated with 0.25 μg of mTOR antibody in 15 μL of buffer A for 1 hour at 4 °C. To each well, 40 μg of HeLa cell lysate in 15 μL of buffer A is added and incubated overnight at 4 °C to immunoprecipitate mTOR complexes. Plates are washed 3 times with buffer A and twice with immunoprecipitation wash buffer [Buffer B: 50 mM HEPES (pH 7.5) and 150 mM NaCl]. OSI-027 is added at 10 μM concentration to each well and DMSO is added to the control wells. The reaction is started by adding 150 ng of His-tagged 4E-BP1 as a substrate in the presence or absence of 100 μM ATP to each well in 25 μL of freshly prepared kinase buffer [Buffer C: 20 mM HEPES (pH 7.5), 10 mM MgCl2, 4 mM MnCl2, 10 mM β-mercaptoethanol, and 200 μM vanadate] and incubated at room temperature (RT) for 30 minutes. The reaction is stopped by transferring 25 μL of reaction mixture from each well to corresponding wells of fresh Ni-chelate-coated plates and incubated overnight at 4 °C followed by 2 hours at 37 °C. To detect phosphorylation of 4E-BP1, the plates are washed once with TBST (Tris-buffered saline containing 0.1% Tween-20) containing 5% skim milk powder. To each well, 25 μL of 1:1,000 diluted phospho-4E-BP1 antibodies in TBST containing 5% skim milk are added and incubated for 1 hour at RT. The plates are washed once with TBST and then 25 μL of anti-rabbit HRP (diluted 1:10,000) in TBST containing 5% skim milk is added. The plates are incubated for 1 hour at RT and washed 5 times with TBST. For detection of phospho-4E-BP1, 25 μL of chemiluminescent reagents A+B is added and chemiluminescence is measured using an Analyst plate reader.

細胞アッセイ:

[2]

細胞系 U937, KG-1, KBM-3B, ML-1, HL-60, and MEG-01
濃度 0-10 μM
処理時間 72 hours
方法

Inhibition of proliferation is measured using the Cell Titer Glo Assay , as noted in figure legends. To generate dose–response curves, cell lines are seeded at a density of 5,000 cells per well in a 96-well plate. After 24 hours of plating, cells are dosed with varying concentrations of either OSI-027 or rapamycin. The signal for Cell Titer Glo Assay is determined 72 hours after dosing and normalized to that of vehicle-treated controls. Inhibition of proliferation, relative to vehicle-treated controls, is expressed as a fraction of 1 and graphed using PRISM software.

動物実験:

[1]

動物モデル GEO colorectal cells are injected s.c. into the right flank of nu/nu CD-1 mice.
製剤 Dissolved in DMSO and then diluted in water.
投薬量 ≤65 mg/kg
管理 Administered via gavage.
1

参考

化学情報

Download OSI-027 SDF
分子量 406.44
化学式

C21H22N6O3

CAS No. 936890-98-1
別名 N/A
溶解度 (25°C)
  • DMSO 18 mg/mL
  • 水 <1 mg/mL
  • エタノール <1 mg/mL
保管 2年 -20°C
6月-80°Cin DMSO
化学名 (1r,4r)-4-(4-amino-5-(7-methoxy-1H-indol-2-yl)imidazo[1,5-f][1,2,4]triazin-7-yl)cyclohexanecarboxylic acid

研究分野

カスタマーレビュー (1)


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Source , , Urol Oncol. 2013 Sep 17. pii: S1078-1439(13)00251-2 . OSI-027 purchased from Selleck
Method Cell proliferation assays
Cell Lines T24, HT1376, and UM-UC-3
Concentrations 0.1-25 uM
Incubation Time 72 h
Results Dual mTOR inhibitor OSI-027 inhibit bladder cancer cell growth in a dose-dependent manner.

製品表彰状 (3)

  • Benzofuran derivatives as a novel class of inhibitors of mTOR signaling [Christophe Salom? et al. European Journal of Medicinal Chemistry 2013;10.1016/j.ejmech.2013.12.020]

  • PI 3-kinase independent role for AKT in F-actin regulation during outer segment phagocytosis by RPE cells. [Bulloj A, et al. Exp Eye Res 2013;113:9-18]

    PubMed: 23669303
  • The combination of an mTORc1/TORc2 inhibitor with lapatinib is synergistic in bladder cancer in vitro. [Becker MN, et al. Urol Oncol 2013;10.1016/j.urolonc.2013.06.002]

    PubMed: 24054871

技術サポート&よくある質問(FAQ)

顧客がするかもしれない質問に対する答えは、指示を取り扱っている阻害剤で見つかります。話題は、貯蔵液(阻害剤と特別な注意を細胞ベースの分析法と動物のために必要とする問題を保存することは実験します)を準備する方法を含みます。

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