Nilotinib (AMN-107) 化学構造
分子量: 529.52

品質と確認

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Quality Control & MSDS

製品情報

  • Combination Therapy
    併用療法
  • Compare Bcr-Abl Inhibitors
    Bcr-Abl阻害剤を比較
  • 研究分野

製品の説明

生物活性

情報 Nilotinib (AMN-107)は、30nM未満のIC50によるBcr-Abl阻害剤です。
目標 Bcr-Abl
IC50 30 nM [1]
In vitro試験 Nilotinib inhibits proliferation, migration, and actin filament formation, as well as the expression of α-SMA and collagen in activated HSCs. Nilotinib induces apoptosis of HSCs, which is correlated with reduced bcl-2 expression, increases p53 expression, cleavage of PARP, as well as increases expression of PPARγ and TRAIL-R. Nilotinib also induces cell cycle arrest, accompanied by increased expression of p27 and downregulation of cyclin D1. Interestingly, Nilotinib not only inhibits activation of PDGFR, but also TGFRII through Src. Nilotinib significantly inhibits PDGF and TGFβ-simulated phosphorylation of ERK and Akt. Furthermore, PDGF- and TGFβ-activated phosphorylated form(s) of Abl in human HSCs are inhibited by Nilotinib. [2] Nilotinib inhibits most imatinib-resistant Bcr-Abl mutations, except for T315I. [3] Nilotinib inhibits PDGF-DD-mediated ERK1/2 activation, basal and PDGF-DD-mediated activation of PDGFRβ and Akt, and schwannoma proliferation. Nilotinib is more potent than imatinib, exerting its maximal inhibitory effect at concentrations lower than steady-state trough plasma levels. [4] Nilotinib also significantly reduces the expression levels of the genes for TGF-β1 and platelet-derived growth factor (PDGF). Nilotinib treatment also significantly inhibits the PDGF-induced proliferation of lung fibroblasts. [5] Nilotinib inhibits the proliferation of Ba/F3 cells expressing p210- and p190-Bcr-Abl, or K562 and Ku-812F cells with IC50 values ≤12 nM. [6]
In vivo試験 Nilotinib reduces collagen deposition and α-SMA expression in CCl4 and BDL-induced fibrosis. Nilotinib could induce HSC undergoing apoptosis, which is correlated with downregulation of bcl-2. [2] Nilotinib attenuates the extent of lung injury and fibrosis. Nilotinib therapy significantly reduces the levels of hydroxyproline on days 14 and 21, which is accompanied by decreased expression levels of transforming growth factor (TGF)-β1 and PDGFRβ. [5] AMN107 prolongs survival of mice injected with Bcr-Abl-transformed hematopoietic cell lines or primary marrow cells, and prolongs survival in imatinib-resistant CML mouse models. [6]
臨床試験 Nilotinib has entered in a phase IV clinical trial in the treatment of philadelphia chromosome positive and chronic myelogenous leukemia in chronic phase.
特集 A selective inhibitor of native and mutant Bcr-Abl.

推薦された実験操作 (公開の文献だけ)

細胞アッセイ: [4]

細胞系 Human primary Schwann and schwannoma cells
濃度 1-10 μM
処理時間 72 hours
方法 Human primary Schwann and schwannoma cells are seeded on precoated 96-well plates. Nilotinib is added 40 minutes before stimulation with 100 ng/mL PDGF-DD, and cells are cultured for 72 hours (3 days). Because the half-life of Nilotinib is 18 hours, one-half of the originally added concentrations are added freshly every day. In addition to DAPI staining and determination of the total cell number, the more sensitive and accurate BrdU incorporation method is used to detect proliferating cells. Total cell amount (DAPI) and number of dividing cells (BrdU-positive) are blindly counted using an inverted fluorescent microscope and 200 × magnification. All cells in every well are counted. The total cell number per well differed between various cell batches and is 100–300 cells/well.

動物実験: [6]

動物モデル Systemic 32D Bcr-Abl leukemia model in Female BALB/c mice, Bioluminescent Bcr-Abl model of CML in Female NOD-SCID mice and Bone marrow transplant Bcr-Abl model of CML in syngeneic Balb/c recipient mice
製剤 10% NMP-90% PEG300, PEG300
投薬量 75 mg/kg, 100 mg/kg
管理 Oral administration
1

参考

化学情報

Download Nilotinib (AMN-107) SDF
分子量 529.52
化学式

C28H22F3N7O

CAS No. 641571-10-0
別名 Tasigna
溶解度 (25°C)
  • DMSO 27 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 4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)benzamide

研究分野

カスタマーレビュー (2)


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Source Leukemia Research, 36 (2012) 1311– 1314. Nilotinib (AMN-107) purchased from Selleck
Method Thymidine uptake Uptake assay
Cell Lines K562, MEG-01 cells
Concentrations 0.1-10uM
Incubation Time 20 min
Results Nilotinib was much more potent than imatinib to inhibit nucleoside transport. It prevented the uptake of thymidine in K562 cells by 97% at 10 uM, a level that was similar to the one obtained with the vasodilatator molecule dipyridamole. Nilotinib was also very efficient at 1 and 0.1 uM; it blocked the entry of thymidine by 90 and 74%, respectively (Fig. 2a). With the MEG-01 cell line, nilotinib was also extremely potent and blocked the entry of thymidine by 96, 92 and 60% with 10, 1 and 0.1 uM nilotinib, respectively (Fig. 2b).

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Rating
Source FASEB J , 2011, 25(10), 3661-3673. Nilotinib (AMN-107) purchased from Selleck
Method Analyzing cell apoptosis
Cell Lines Ba/F3-p210T315I cells
Concentrations 0-5 μM
Incubation Time 24 h
Results In a parallel study using imatinib/PDMP or nilotinib/PDMP combinations, to our surprise, similar significant synergy in Ba/F3-p210T315I cells was observed.

製品表彰状 (5)

  • Glucosylceramide synthase inhibitor PDMP sensitizes chronic myeloid leukemia T315I mutant to Bcr-Abl inhibitor and cooperatively induces glycogen synthase kinase-3-regulated apoptosis. [Huang WC, et al. FASEB J 2011;25(10):3661-73]

    PubMed: 21705667
  • Simultaneous quantification of ruxolitinib and nilotinib in rat plasma by LC–MS/MS: Application to a pharmacokinetic study [Sridhar Veeraraghavan J PHARMACEUT BIOMED 2014;10.1016/j.jpba.2014.01.040]

  • Imatinib and Nilotinib inhibit Bcr-Abl-induced ROS through targeted degradation of the NADPH oxidase subunit p22phox. [Landry WD, et al. Leuk Res 2012;37(2):183-9]

    PubMed: 23218026
  • Nilotinib and imatinib inhibit cytarabine cellular uptake: Implications for combination therapy. [Naud JS, et al. Leuk Res 2012;36(10):1311-4]

    PubMed: 22796208
  • Nilotinib-induced autophagic changes increase endogenous parkin level and ubiquitination, leading to amyloid clearance [Irina Lonskaya, et al. Journal of Molecular Medicine 2013;10.1007/s00109-013-1112-3]

    PubMed: 24337465

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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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