Linifanib (ABT-869)

Linifanib(ABT-869)は、新しい、強力なATP競争的RTK阻害剤で、KDRCSF-1RFlt-1Flt-3に作用するとき、IC50がそれぞれ 4 nM、 3 nM、 3 nM 、3 nMになる。

目録号S1003
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Linifanib (ABT-869) 化学構造
分子量: 375.41

品質と確認

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Quality Control & MSDS

製品情報

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

製品の説明

生物活性

情報 Linifanib(ABT-869)は、新しい、強力なATP競争的RTK阻害剤で、KDRCSF-1RFlt-1Flt-3に作用するとき、IC50がそれぞれ 4 nM、 3 nM、 3 nM 、3 nMになる。
目標 KDR CSF-1R Flt-1 Flt-3 PDGFRβ
IC50 4 nM 3 nM 3 nM 4 nM 66 nM [1]
In vitro試験 Linifanib shows inhibitory to Kit, PDGFRβ and Flt4 with IC50 of 14 nM, 66 nM and 190 nM in kinases assay. Linifanib also inhibits ligand-induced KDR, PDGFRβ, Kit, and CSF-1R phosphorylation with IC50 of 2 nM, 2 nM, 31 nM and 10 nM at cellular level and this cellular potency could be affected by serum protein. Linifanib suppresses VEGF-stimulated HUAEC proliferation with IC50 of 0.2 nM. While Linifanib has weak activity against tumor cells which are not induced by VEGF or PDGF, except for MV4-11 leukemia cells (with constitutively active form of Flt3) with IC50 of 4 nM. Linifanib could cause a decrease in S and G2-M phases with a corresponding increase in the sub-G0-G1 apoptotic population in MV4-11 cells. [1] Linifanib binds to the ATP-binding site of CSF-1R with Ki of 3 nM. [2] Linifanib (10 nM) exhibits a reduced phosphorylation of Akt at Ser473 and decreased phosphorylation of GSK3βat Ser9 in Ba/F3 FLT3 ITD cell lines. [3]
In vivo試験 Linifanib (0.3 mg/kg) results in complete inhibition of KDR phosphorylation in lung tissue. Linifanib also inhibits the edema response with ED50 of 0.5 mg/kg. Linifanib (7.5 and 15 mg/kg, bid) significantly inhibits both bFGF- and VEGF-induced angiogenesis in the cornea. Linifanib inhibits tumor growth in flank xenograft models including HT1080, H526, MX-1 and DLD-1 with ED75 from 4.5-12 mg/kg. Linifanib also shows efficacy in A431 and MV4-11 xenografts at low dose levels. Linifanib (12.5 mg/kg bid) reveals a decrease of microvasculure density in MDA-231 xenograft. Linifanib shows a Cmax and AUC24 hours with 0.4 μg/mL and 2.7 μg•hour/mL in HT1080 fibrosarcoma model. [1]
臨床試験 Linifanib is in a Phase III evaluation for hepatocellular carcinoma.
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 Potencies (IC50 values) are determined by assays of active kinase domains cloned and expressed in baculovirus using the FastBacbaculovirus expression system or obtained commercially. For tyrosine kinase assays, a biotinylated peptide substrate containing a single tyrosine is used with 1 mM ATP, anEu-cryptate–labeled anti-phosphotyrosine antibody (PT66), and Strepavidin-APC in a homogeneous time-resolved fluorescence assay. Serine/threonine kinases are assayed using 5 μM ATP, [33P]ATP, and a biotinylated peptide substrate with peptide capture and incorporation of 33P determined using a SA-Flashplate. Linifanib is assayed at multiple concentrations prepared by serial dilution of a DMSO stock solution of Linifanib. The concentration resulting in 50% inhibition of activity is calculated using nonlinear regression analysis of the concentration response data.

細胞アッセイ: [1]

細胞系 HUAEC, HT-29, HT1080, A431, MDA-435, MDA-231, H526, DLD-1, 9L and MV4-11 cells
濃度 0-100 μM
処理時間 72 hours
方法 Cells are seeded into 96-well plates at 2.5 × 103 per well and incubated with serum-free medium for 24 hours. Linifanib and VEGF (final, 10 ng/mL) are added and incubated for 72 hours in serum-free medium. For carcinoma cell lines, 3 × 103 cells/well are plated overnight in full growth medium. Linifanib is added to the cells in full growth medium and incubated for 72 hours. For leukemia cells, generally 5 × 104 per well are plated in full growth medium, Linifanib is added, and incubated for 72 hours. The effects on proliferation are determined by addition of Alamar Blue (final solution, 10%), incubation for 4 hours at 37 °C in a CO2 incubator and analysis in a fluorescence plate reader (544 nm, excitation: 590 nm, emission

動物実験: [1]

動物モデル H526, DLD-1, MDA-231, MDA-435LM, HCT-116, H526, DLD-1, MDA-231, MDA-435LM, MV4-11 and MX-1 xenografts are established in mice.
製剤 2% ethanol, 5% Tween 80, 20% PEG400, 73% saline
投薬量 ~ 10 mg/kg
管理 Oral administration
Solubility 30% PEG400/0.5% Tween80/5% propylene glycol, 30 mg/mL
* 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.
1

参考

化学情報

Download Linifanib (ABT-869) SDF
分子量 375.41
化学式

C21H18FN5O

CAS No. 796967-16-3
保管 2年-20℃
6月-80℃in DMSO
別名 AL-39324
溶解度 (25°C) * In vitro DMSO 75 mg/mL (199 mM)
<1 mg/mL (<1 mM)
エタノール <1 mg/mL (<1 mM)
In vivo 30% PEG400/0.5% Tween80/5% propylene glycol, 30 mg/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 1-(4-(3-amino-1H-indazol-4-yl)phenyl)-3-(2-fluoro-5-methylphenyl)urea

研究分野

カスタマーレビュー (3)


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Source J Pharmacol Exp Ther, 2012, 343(3), 617-27. Linifanib (ABT-869) purchased from Selleck
Method ELISA/Kinase Assays
Cell Lines Mice-bearing tumors
Concentrations 25 mg/kg
Incubation Time 0-7 day
Results ABT-348 inhibited the VEGF response with a potency (ED 50 = 0.2 mg/kg i.v.) that is comparable with another potent anti-VEGF agent, ABT-869, which has intrinsic VEGFR2 potency similar to ABT-348 (IC 50 = 4 and 3 nM, respectively). On-target VEGF receptor inhibition was also implicated by the observation that administration of ABT-348 to tumor-bearing mice resulted in increased plasma levels of the proangiogenic PLGF (Fig. B). acute changes in the MRI signal were observed during treatment with ABT-348 (Fig. C). After a sharp decrease in Ktrans that was apparent within 24 h after the first treatment cycle of ABT-348, the MRI signal returned to pretreatment levels by 6 days when reassessed longitudi-nally, which was reflective of the Q7D-dosing sequence. (Fig. D) the reduction in Ktrans (75%) was similar in magnitude to that previously reported for the selective EGFR/PDGFR inhibitor.

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Source Liver Int, 2011, 32(3), 400-409. Linifanib (ABT-869) purchased from Selleck
Method Quantification of apoptosis, TUNEL assay
Cell Lines KMCH-1 cells, LX-2 cells
Concentrations 0.5 µmol/L
Incubation Time 24 h
Results KMCH-1 cells were more resistant to TRAIL-induced apoptosis when co-cultured with LX-2 cells when compared with monoculture conditions, a cytoprotective effect that was significantly attenuated by Linifanib.

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Source Dr. Zhang of Tianjin Medical University. Linifanib (ABT-869) purchased from Selleck
Method Western blotting
Cell Lines T47D breast cancer cells
Concentrations 0-2.5 μM
Incubation Time
Results ABT-869 increased protein expression levels of Bcl-xl and Bcl2 in T47D breast cancer cells.

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