Masitinib (AB1010)

Masitinib (AB1010)は一種の新たなKitとPDGFRα/β阻害剤で、IC50値が200 nMと540 nM/800 nMに分かれることです。Masitinib (AB1010)はABLとc-Fmsを抑制する効果が少し弱いです。臨床3期。

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Masitinib (AB1010) 化学構造
分子量: 498.64

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製品説明

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製品の説明

生物活性

製品説明 Masitinib (AB1010)は一種の新たなKitとPDGFRα/β阻害剤で、IC50値が200 nMと540 nM/800 nMに分かれることです。Masitinib (AB1010)はABLとc-Fmsを抑制する効果が少し弱いです。臨床3期。
ターゲット Kit PDGFRα/β
IC50 200 nM 540 nM/800 nM [1]
In vitro試験 Masitinib is a competitive inhibitor against ATP at concentrations ≤500 nM. Masitinib also potently inhibits recombinant PDGFR and the intracellular kinase Lyn, and to a lesser extent, fibroblast growth factor receptor 3. In contrast, Masitinib demonstrates weak inhibition of Abl and c-Fms. Masitinib more strongly inhibits degranulation, cytokine production, and bone marrow mast cell migration than imatinib. In Ba/F3 cells expressing human wild-type Kit, Masitinib inhibits SCF (stem cell factor)-induced cell proliferation with an IC50 of 150 nM, while the IC50 for inhibition of IL-3-stimulated proliferation is at approximately >10 µM. In Ba/F3 cells expressing PDGFRα, Masitinib inhibits PDGF-BB-stimulated proliferation and PDGFRα tyrosine phosphorylation with IC50 of 300 nM. Masitinib also causes inhibition of SCF-stimulated tyrosine phosphorylation of human Kit in mastocytoma cell-lines and BMMC. Masitinib inhibits Kit gain-of-function mutants, including V559D mutant and Δ27 mouse mutant with IC50 of 3 and 5 nM in Ba/F3 cells. Masitinib inhibits the cell proliferation of mastocytoma cell lines including HMC-1α155 and FMA3 with IC50 of 10 and 30 nM, respectively. [1] Masitinib inhibits cell growth and PDGFR phosphorylation in two novel ISS cell lines, which suggest that Masitinib displays activity against both primary and metastatic ISS cell line and may aid in the clinical management of ISS. [2]
In vivo試験 Masitinib inhibits tumour growth and increases the median survival time in Δ27-expressing Ba/F3 tumor models at 30 mg/kg, without cardiotoxicity or genotoxicity. [1] Masitinib (12.5 mg/kg/d PO) increases overall TTP (time-to-tumor progression) compared with placebo in dogs. [3] The combination of masitinib/gemcitabine shows synergy in vitro on proliferation of gemcitabine-refractory cell lines Mia Paca2 and Panc1, and to a lesser extent on Mia Paca-2 pancreatic tumours in Nog璖CID mice. [4]
臨床試験 Currently in Phase III to compare the efficacy and the safety of Masitinib versus Placebo in the treatment of patients with severe persistent asthma treated with oral corticosteroids
特集 Potential low side-effect profile.

プロトコル (参考用のみ)

キナーゼアッセイ: [1]

In vitro enzyme-linked immunoassay with recombinant protein kinases A 96-well microtitre plateis coated overnight with 0.25 mg/ml poly(Glu,Tyr 4:1), rinsed twice with 250 µL of washing buffer (10 mM phosphate-buffered saline [pH 7.4] and 0.05% Tween 20) and dried for 2 hours at room temperature. Assays are performed at room temperature with a final volume of 50 µL in kinase buffer (10 mM MgCl2, 1 mM MnCl2, 1 mM sodium orthovanadate, 20 mM HEPES, pH 7.8) containing ATP at a concentration of at least twice the Km for each enzyme and an appropriate amount of recombinant enzyme to ensure a linear reaction rate. Reactions are initiated upon introduction of the enzyme and terminated with the addition of one reaction volume (50 μL) of 100 mM EDTA per 5 M urea mix. Plates are washed three times and incubated with 1:30,000 horseradish peroxidase-conjugated anti-phosphotyrosine monoclonal antibody, then washed three times and incubated with tetramethylbenzidine. The final reaction product is quantified by spectrophotometry at 450 nm.

細胞アッセイ: [1]

細胞株 Ba/F3 cells expressing wild-type or mutant human Kit, HMC1, HMC-1α155
濃度 0.1 nM - 10 μM
反応時間 48 hours
実験の流れ For the assay of Ba/F3 cell proliferation, microtitre plates are seeded with a total of 104 cells/well in 100 μL of RPMI 1640 medium with 10% foetal bovine serum at 37 °C. These are supplemented, or not, with either 0.1% conditioned medium from X63-IL-3 cells or 250 ng/mL murine SCF. The murine SCF, which activates Kit, is purified from the conditioned medium of SCF-producing CHO cells. Cells are grown for 48 hours at 37 °C with Masitinib and then incubated with 10 μL/well of WST-1 reagent for 3 hours at 37 °C. The amount of formazan dye formed is quantified by its absorbance at 450 nm using a scanning multiwell spectrophotometer. A blank well without cells is used as a background control for the spectrophotometer.

動物実験: [1]

動物モデル Ba/F3 Δ27 tumour model in female MBRI Nu/Nu mice
製剤 DMSO
投薬量 30 mg/kg (intraperitoneal) or 10, 30, or 45 mg/kg (orally).
投与方法 Intraperitoneal or orally administered.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

参考

化学情報

Download Masitinib (AB1010) SDF
分子量 498.64
化学式

C28H30N6OS

CAS No. 790299-79-5
保管 3年-20℃
2年-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 100 mg/mL (200.54 mM)
Ethanol 4 mg/mL (8.02 mM)
Water <1 mg/mL
In vivo 4% DMSO+30% PEG 300+5% Tween 80+ddH2O 30mg/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 N-(4-methyl-3-(4-(pyridin-3-yl)thiazol-2-ylamino)phenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide

文献中の引用 (6)

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