Masitinib 是生物口服可利用的选择性c-Kit抑制剂 (对于人重组c-Kit，IC50=200 nM)，它还抑制PDGFRα/β(IC50s=540/800 nM)，Lyn(对 LynB 的IC50=510 nM)，Lck，较小程度上抑制FGFR3和FAK。它有抗增殖，促凋亡活性，且毒性低。

Masitinib is a tyrosine-kinase inhibitor used in the treatment of mast cell tumors in animals, specifically dogs. Since its introduction in November 2008 it has been distributed under the commercial name Masivet. It has been available in Europe since the second part of 2009. In the USA it is distributed under the name Kinavet and has been available for veterinaries since 2011.

与安慰剂相比,Masitinib（12.5 mg/kg/d PO）可增加狗的总体TTP（肿瘤进展时间）.在表达Δ27的Ba/F3 移植瘤模型中,30 mg/kg Masitinib抑制肿瘤生长和提高平均存活时间,没有心脏毒性或遗传毒性.Masitinib和吉西他滨联用表现出对抗吉西他滨的细胞系Mia Paca2和Panc1增殖的协同抑制作用.

Masitinib抑制表达人类野生型KIT的Ba/F3的细胞中干细胞因子诱导的细胞增殖,IC50为150 nM,而抑制IL-3刺激的增殖时,IC50值约>10 μM。Masitinib在表达PDGFR-α的Ba/F3细胞中,抑制PDGF-BB刺激的增殖和 PDGFR-α 酪氨酸磷酸化作用,IC50为300 nM。Masitinib浓度≤500 nM时为ATP竞争性抑制剂。Masitinib也有效抑制重组PDGFR和胞内激酶Lyn及FGFR 3。 然而,Masitinib对ABL和c-Fms抑制效果很弱。在哺乳动物细胞系和BMMC中,马西替尼还能抑制SCF刺激的人Kit酪氨酸磷酸化。Masitinib抑制Ba/F3细胞中KIT获得的功能突变,包括V559D突变和Δ27鼠突变,IC50分别为3和5 nM。在两种新型ISS细胞系中,Masitinib抑制细胞生长和PDGFR磷酸化,这表明Masitinib显示针对原发性和转移性ISS细胞系的活性,并可能有助于ISS的临床管理。Masitinib对脱颗粒,细胞因子产生和骨髓肥大细胞迁移的抑制效果比imatinib强很多。Masitinib抑制肥大细胞瘤细胞系包括 HMC-1α155和FMA3的细胞增殖,IC50分别为10和30 nM。

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.

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. (Only for Reference)

790299-79-5

C28H30N6OS

498.65

马赛替尼;AB1010

DMSO:93 mg/mL (186.5 mM)
H2O:<1 mgml
Ethanol:4 mg/mL (8.02 mM)
Powder: -20°C for 3 years
In solvent: -80°C for 2 years