Ibrutinib (PCI-32765)

Ibrutinib (PCI-32765)は、0.5nMのIC50による有力で非常に選択的なブラットンのチロシン・キナーゼ(Btk)阻害剤です。

目録号S2680
5 5 3レビュー 8製品表彰状
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Ibrutinib (PCI-32765) 化学構造
分子量: 440.5

品質と確認

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Quality Control & MSDS

製品情報

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  • 研究分野

製品の説明

生物活性

情報 Ibrutinib (PCI-32765)は、0.5nMのIC50による有力で非常に選択的なブラットンのチロシン・キナーゼ(Btk)阻害剤です。
目標

Btk

IC50

0.5 nM [1]

In vitro試験 Ibrutinib shows the potent and irreversible inhibitory effect and selectivity for Btk enzymatic activity. In BCR pathway-activated DOHH2 cell line, Ibrutinib inhibits autophosphorylation of Btk, phosphorylation of Btk's physiological substrate PLCγ, and phosphorylation of further downstream kinase, ERK with IC50 of 11 nM, 29 nM and 13 nM, respectively. [1] Ibrutinib exhibits a significant dose-dependent and time-dependent induction of cytotoxicity in chronic lymphocytic leukemia (CLL) cells. In addition, Ibrutinib induces cell death depending on caspase pathway activation and antagonizes the ability of CLL cells to proliferate after TLR signaling. [2] A recent study shows that Ibrutinib inhibits BCR-activated primary B cell proliferation with IC50 of 8 nM and results in inhibition of TNFα, IL-1β and IL-6 production in primary monocytes with IC50 of 2.6 nM, 0.5 nM and 3.9 nM, respectively. [3]
In vivo試験 In a collagen-induced arthritis model, Ibrutinib significantly reduces clinical arthritis scores reflecting paw swelling and joint inflammation by inhibiting B-cell activation. In a MRL-Fas(lpr) lupus model, Ibrutinib reduces renal disease and autoantibody production. [1] In an adoptive transfer TCL1 mouse model of CLL, Ibrutinib (25 mg/kg/day) causes a transient early lymphocytosis, and delays CLL disease progression. [4]
臨床試験 Ibrutinib is currently in Phase II clinical trials in patients with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). Combination of Ibrutinib and Rituximab is currently in Phase II clinical trials in patients with High-Risk Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL).
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]

Kinase Assays In vitro kinase IC50 values are measured using 33P filtration binding assay after 1 hour incubation of kinase, 33P-ATP, Ibrutinib, and substrate [0.2 mg/mL poly(EY)(4:1]. Assays are performed at Reaction Biology.

細胞アッセイ:

[2]

細胞系 Chronic lymphocytic leukemia (CLL) cells
濃度 0.01-100 μM
処理時間 48 hours
方法

MTT (3'[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) assays are performed to determine cytotoxicity. Briefly, cells (CLL B cells or healthy volunteer T cells or NK cells) are incubated for 48 hours with different concentrations of Ibrutinib, or vehicle control. MTT reagent is then added, and plates are incubated for an additional 20 hours before washing with protamine sulfate in phosphate-buffered saline. Dimethyl sulfoxide is added, and absorbance is measured by spectrophotometry at 540 nm in a Labsystems plate reader. Cell viability is also measured at various time points with the use of annexin/PI flow cytometry. Data are analyzed with Expo-ADC32 software package. Results are expressed as the percentage of total positive cells over untreated control. Experiments examining caspase-dependent apoptosis includes the addition of 100μM Z-VAD.

動物実験:

[1]

動物モデル MRL-Fas(lpr) lupus model and collagen-induced arthritis model.
製剤 Ibrutinib is dissolved in DMSO.
投薬量 ≤50 mg/kg
管理 Administered via p.o.
1

参考

化学情報

Download Ibrutinib (PCI-32765) SDF
分子量 440.5
化学式

C25H24N6O2

CAS No. 936563-96-1
別名 N/A
溶解度 (25°C)
  • DMSO 88 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 (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one

研究分野

カスタマーレビュー (3)


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Rating
Source Cell Signal, 2013, 25(1), 106-12.. Ibrutinib (PCI-32765) purchased from Selleck
Method Western blotting/Proliferation/death assays
Cell Lines MM cell lines
Concentrations 1/10 μM
Incubation Time 48 h
Results Ibrutinib induces signifi cant cell death (7–46%) in MM cells at 10 μM(Fig. C) as measured by the Cell Titer GLO assay. We also observed a similar effect with ibrutinib in MM cell lines ( Fig. D).

Click to enlarge
Rating
Source Cell Signal, 2013, 25(1), 106-12.. Ibrutinib (PCI-32765) purchased from Selleck
Method flow cytometry/Cell Titer GLO assay
Cell Lines RPMI8226 cells/Primary human monocytes
Concentrations 1/10 μM
Incubation Time 48 h
Results Ibrutinib significantly increased cytotoxicity of malignant plasma cells, with the effectin- vitro appearing greater in combination with bortezomib (Fig. A). We also observed a similar effect with ibrutinib in combination with either lenalidomide or bortezomi b in MM ce ll lines (Fig. B). These observations were further confirmed using an annexin-V/ propidium iodide apoptosis assay (Fig. C). Furthermore, we observed that BTK inhibition had no cytotoxic effects on primary monocytes suggesting the effect on malignant plasma cells is not through non-specific cytotoxicity (Fig. D).

Click to enlarge
Rating
Source Cell Signal, 2013, 25(1), 106-12.. Ibrutinib (PCI-32765) purchased from Selleck
Method Western blotting/Cell Titer GLO assay/Real-time PCR
Cell Lines MM cells
Concentrations 10 μM
Incubation Time 48 h
Results We found that FLIPL, Bcl-xL and survivin are inhibited by ibrutinib alone and in combination with bortezomib (Fig. A and B). Since both FLIPL and Bcl-xL negatively regulate caspase-induced cell death we looked to establish whether cell death observed in the MM cells was the result of caspase activation. Thepan-caspase inhibitor zVAD-fmk was able to protect MM cells from cell death induced by ibrutinib alone or in co mb in ation with bortezomib establishing that ibrutinib induced MM cell death is caspase-dependent(Fig. C).

製品表彰状 (8)

  • Crosstalk between ROR1 and the Pre-B Cell Receptor Promotes Survival of t (1; 19) Acute Lymphoblastic Leukemia. [Bicocca VT, et al. Cancer Cell 2012;22(5):656-67]

    PubMed: 23153538
  • Identification of Bruton's tyrosine kinase as a therapeutic target in acute myeloid leukemia. [Rushworth SA, et al. Blood 2013;10.1182/blood-2013-06-511154]

    PubMed: 24307721
  • B-cell receptor triggers drug sensitivity of primary CLL cells by controlling glucosylation of ceramides. [Schwamb J, et al. Blood 2012;120(19):3978-85]

    PubMed: 22927247
  • BTK inhibitor ibrutinib is cytotoxic to myeloma and potently enhances bortezomib and lenalidomide activities through NF-κB. [Rushworth SA, et al. Cell Signal 2013;25(1):106-12]

    PubMed: 22975686
  • Bruton’s Tyrosine Kinase Mediates the Synergistic Signalling between TLR9 and the B Cell Receptor by Regulating Calcium and Calmodulin. [Kenny EF, et al. PLoS One 2013;8(8): e74103]

    PubMed: 23967355
  • Nuclear Translocation of B-Cell-Specific Transcription Factor , BACH2, Modulates ROS Mediated Cytotoxic Responses in Mantle Cell Lymphoma. [Zheng Chen, et al. PLoS ONE 2013;8(8):e69126]

    PubMed: 23936317
  • Bruton tyrosine kinase is commonly overexpressed in mantle cell lymphoma and its attenuation by Ibrutinib induces apoptosis. [Cinar M, et al. Leuk Res 2013;37(10):1271-7]

    PubMed: 23962569
  • Interference with pre-B-cell receptor signaling offers a therapeutic option for TCF3-rearranged childhood acute lymphoblastic leukemia [van der Veer A Blood Cancer J 2014;10.1038/bcj.2014.5]

    PubMed: 24531445

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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