Rebastinib (DCC-2036)

製品コードS2634

Rebastinib (DCC-2036)化学構造

分子量(MW):553.59

Rebastinib (DCC-2036)は一種のBcr-Abl阻害剤で、Abl1(WT)とAbl1(T315I)に作用する時のIC50値が0.8 nMと4 nMです。DCC-2036 (Rebastinib)はSRC、LYN、FGR、HCK、KDR、FLT3とTie-2も抑制しますが、c-Kitに低い抑制活性を表します。臨床1期。

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カスタマーフィードバック(2)

  • BaF3-T674I cells were exposed to the indicated concentrations of DCC-2036, imatinib or sorafenib for 36 h, the phosphorylated PDGFRα and total PDGFRα were analyzed by immunoblotting. Imatinib was used for comparison.

    PLoS One 2013 8, e73059. Rebastinib (DCC-2036) purchased from Selleck.

    Immunohistochemical analysis of Ki67 in xenograft tissues from mice. Hematoxylin and eosin (H&E)-stained serial sections of the same xenografts are presented.

    PLoS One 2013 8, e73059. Rebastinib (DCC-2036) purchased from Selleck.

製品安全説明書

Bcr-Abl阻害剤の選択性比較

生物活性

製品説明 Rebastinib (DCC-2036)は一種のBcr-Abl阻害剤で、Abl1(WT)とAbl1(T315I)に作用する時のIC50値が0.8 nMと4 nMです。DCC-2036 (Rebastinib)はSRC、LYN、FGR、HCK、KDR、FLT3とTie-2も抑制しますが、c-Kitに低い抑制活性を表します。臨床1期。
特性 A conformational control inhibitor of Abl1 and T315I Abl1.
靶点
u-Abl1 (native) [1] Abl1 (H396P) [1] p-Abl1 (native) [1] FLT3 [1] p-Abl1 (T315I) [1]
0.75 nM 1.4 nM 2 nM 2 nM 4 nM
In vitro試験

DCC-2036 shows the potent inhibitory activities against purified native Abl1 in unphosphorylated (u-Abl1native) and phosphorylated (p-Abl1native) forms, unphosphorylated and phosphorylated gatekeeper mutant Abl1T315I, and the activation loop mutant Abl1H396P in a non-ATP-competitive manner with IC50 of 0.8 nM, 2 nM, 1.4 nM, 5 nM, and 4 nM, respectively. Moreover, DCC-2036 also inhibits the Src family kinases Src, LYN, FGR, and HCK, and the receptor TKs KDR, FLT3, and TIE2 with IC50 of 34 nM, 29 nM, 38 nM, 40 nM, 4 nM, 2 nM and 6 nM, respectively. [1] DCC-2036 shows the anti-proliferative activities against Ba/F3 cells expressing native or mutant Bcr-Abl1 with IC50 ranging from 2 nM to 150 nM. In addition, DCC-2036 also inhibits proliferation of the Ph+ cell line K562 (IC50 5.5 nM), and induces apoptosis in both Bcr-Abl1-expressing Ba/F3 and K562 cells potently. [1] A recent study shows that DCC-2036 shows the selectivity for growth inhibition of Bcr-Abl-positive cells by its marked inhibition of CML cell lines compared to non-CML leukemia lines. [2]

In vivo試験 In a mouse allograft model bearing Ba/F3-Bcr-Abl1T315I leukemia cells, DCC-2036 treatment by oral gavage at 100 mg/kg once daily effectively inhibits Bcr-Abl1 signaling and significantly prolongs mouse survival. [1]

プロトコル(参考用のみ)

キナーゼアッセイ:[1]
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Assay of Abl1 kinase isoforms and determination of inhibitor potency:

Activity of u-Abl1native is determined by following the production of ADP from the kinase reaction through coupling with the pyruvate kinase/lactate dehydrogenase system. In this assay, the oxidation of NADH (measured as a decreased A340nm) is continuously monitored spectrophotometrically. The final reaction mixture (100 μL, in a 384-well Corning plate) is prepared as follows: An Abl1 kinase/coupled assay components mixture is prepared containing u-Abl1 kinase (1 nM), Abltide (EAIYAAPFAKKK, 0.2 mM), MgCl2 (9 mM), pyruvate kinase (~ 4 units), lactate dehydrogenase (~ 0.7 units), phosphoenol pyruvate (1 mM), and NADH (0.28 mM) in 90 mM Tris containing 0.1 % octyl-glucoside and 1 % DMSO, pH 7.5. Separately, an inhibitor mixture is prepared containing DCC-2036 serially diluted 3-fold in DMSO followed by dilution into buffer composed of 180 mM Tris, pH 7.5, containing MgCl2 (18 mM) and 0.2 % octyl-glucoside. Fifty μL of the inhibitor mixture is mixed with 50 μL of the above Abl1 kinase/coupled assay components mixture, which is then incubated at 30 °C for 2 hours before 2 μL of 25 mM ATP (500 μM, final) is added to start the reaction. The reaction is recorded every 2 minutes for 2.5 hours at 30 °C on a Polarstar Optima or Synergy2 plate reader. Reaction rate (slope) is calculated using the 1 to 2 hour time frame with reader's software. Percent inhibition is obtained by comparison of reaction rate with that of a DMSO control. IC50 values are calculated from a series of percent inhibition values determined at a range of inhibitor concentrations using GraphPad Prism. The kinase assay for Abl1T315I, p-Abl1native or Abl1H396P is assayed the same as above except that 2.2 nM Abl1T315I, 1 nM p-Abl1 native or 1.3 nM Abl1H396P is used. The above assay format is also used for kinases other than Abl1 with the exception of TIE2, for which a fluorescence polarization/Transcreener format is used. The assay conditions are the same as described above except that PolyE4Y (final 1 mg/mL) is used as the substrate and one hour preincubation is used.
細胞アッセイ: [1]
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  • 細胞株: Ba/F3 cells and primary Ph+ leukemia cells
  • 濃度: 0-10 μM
  • 反応時間: 72 hours
  • 実験の流れ: Ba/F3 cells or primary Ph+ leukemia cells are plated in triplicate in 96-well plates containing test compounds. After 72 hours, viable cells are quantified by Resazurin or MTT assay. Cells are diluted in medium to be added to each well of a 96-well tissue culture-treated plate. All cells are incubated overnight and maintained in a humidified atmosphere at 37 °C and 5% CO2. Cells are treated the following day. Serum-free medium is used during treatment with DCC-2036. MTT is used to assess the viability of cells following treatment. Aliquots of 20 mL of stock MTT solution are added to each well containing 200 mL of medium (10% final solution) and incubated with the cells for 2 hours. Following incubation the medium is removed and 200 mL of dimethylsulfoxide added to solubilize the formazan crystals. The absorbance is read on the plate reader at 550 and 690 nm. A subtraction analysis of the dual wavelength is performed (D550 to D690) to increase accuracy of the measuremen
    (参考用のみ)
動物実験:[1]
+ 展開
  • 動物モデル: Ba/F3 cells transformed to interleukin-3 independence by transduction with either Bcr-Abl1native or Bcr-Abl1T315I retrovirus are injected intravenously into syngeneic Balb/c mice.
  • 製剤: DCC-2036 is dissolved in 0.5% CMC/1% Tween-80.
  • 投薬量: ≤100 mg/kg
  • 投与方法: Administered via p.o.
    (参考用のみ)

溶解度 (25°C)

体外 DMSO 111 mg/mL (200.5 mM)
Ethanol 16 mg/mL (28.9 mM)
Water <1 mg/mL
体内 0.5% CMC+0.25% Tween 80 16 mg/mL

* <1 mg/mlは製品が微弱に溶解する或いは溶解しないことを示します。
* 溶解度検測はSelleck技術部門によって行いますので、文献より提供された溶解度と差異がある可能性がありますが、生産工芸と不同ロット(lot)で起きる正常な現象ですから、ご安心ください。

化学情報

分子量 553.59
化学式

C30H28FN7O3

CAS No. 1020172-07-9
保管
in solvent
別名 N/A

便利ツール

モル濃度計算器

モル濃度計算器

解決のために必要とされるマス、ボリュームまたは濃度を計算してください。

マス (g) = 濃度 (mol/L) x ボリューム (L) x 分子量 (g/mol)

モル濃度計算器方程式

  • マス
    濃度
    ボリューム
    分子量

*貯蔵液を準備するとき、常に、オンであるとわかる製品のバッチに特有の分子量を使って、を通してラベルとMSDS/COA(製品ページで利用可能な)。

希釈計算器

希釈計算器

貯蔵液を準備することを要求される希釈剤を計算してください. セレック希釈計算器は、以下の方程式に基づきます:

開始濃度 x 開始体積 = 最終濃度 x 最終体積

希釈の計算式

この方程式は、一般に略語を使われます:C1V1 = C2V2 ( 輸入 輸出 )

  • C1
    V1
    C2
    V2

常に貯蔵液を準備するとき、小びんラベルとMSDS/COA(オンラインで利用できる)で見つかる製品のバッチに特有の分子量を使ってください。

連続希釈計算器方程式

  • 連続希釈剤

  • 計算結果

  • C1=C0/X C1: LOG(C1):
    C2=C1/X C2: LOG(C2):
    C3=C2/X C3: LOG(C3):
    C4=C3/X C4: LOG(C4):
    C5=C4/X C5: LOG(C5):
    C6=C5/X C6: LOG(C6):
    C7=C6/X C7: LOG(C7):
    C8=C7/X C8: LOG(C8):
分子量計算器

分子量计算器

そのモル質量と元素組成を計算するために、合成物の化学式を入力してください:

総分子量:g/mol

チップス: 化学式は大文字と小文字の区別ができます。C10H16N2O2 c10h16n2o2

モル濃度計算器

マス 濃度 ボリューム 分子量

臨床試験

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT02824575 Recruiting Breast Cancer|Breast Adenocarcinoma|Human Epidermal Growth Factor 2 Negative Carcinoma of Breast|Recurrent Breast Carcinoma|Stage IV Breast Cancer Montefiore Medical Center|Deciphera Pharmaceuticals LLC|Albert Einstein College of Medicine of Yeshiva University July 2016 Phase 1
NCT00827138 Completed Chronic Myeloid Leukemia Deciphera Pharmaceuticals LLC March 2009 Phase 1

技術サポート

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Handling Instructions

他の質問がある場合は、お気軽くお問合せください。

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID