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Bafetinib

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Chemical Structure| 859212-16-1 同义名 : INNO-406;NS-187
CAS号 : 859212-16-1
货号 : A124910
分子式 : C30H31F3N8O
纯度 : 98+%
分子量 : 576.615
MDL号 : MFCD18633200
存储条件：

粉末 Keep in dark place,Sealed in dry,Store in freezer, under -20°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 105 mg/mL(182.1 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：

0.5% methylcellulose+0.2% Tween 80+water 30 mg/mL suspension

生物活性
靶点

  • Abl

    Abl, IC50:5.8 nM
描述 The oncogenic tyrosine kinase Bcr-Abl plays a central role in the pathogenesis of chronic myelogenous leukemia, thus makes it as the therapy drug target. However, it is demonstrated that the mutations of Bcr-Abl kinase have been the most common mechanism of drug resistance, such as imatinib. Bafetinib is dual Abl/Lyn inhibitor with IC50 values of 5.8nM and 19nM (measured by kinase activity), respectively. Further in vitro kinase assays showed that Bafetinib can inhibit almost all Bcr-Abl point mutants tested, including M244V, G250E, Q252H, Y253F, E255K, E255V, F317L, M351T, E355G, E359V, H396P and F486S at concentration ranging in 81-1400nM. Compared with imatinib, Bafetinib can block cellular autophosphorylation of Abl-wt, Bcr-Abl and its mutation E255K, but not T315I, at much lower concentration ranging in 11-340nM, whereas the inhibitory effect against PDGFR and c-Kit by Bafetinib was very similar to imatinib. Consistent with this, obvious dephosphorylation of the downstream mediators of Bcr-Abl or the mutant E255K, including p-CrkL and p-ERK by Bafetinib occurred at concentration of 0.1-10μM in cells, almost 10 fold less than imatinib. The anti-proliferative effect by Bafetinib can also observed at low micromolar concentration in Bcr-Abl–positive cell lines K562, KU812 and BaF3/wt. In vivo studies showed that Bafetinib can significantly inhibited tumor growth at dose of only 0.2 mg/kg/d, whereas dose at 20 mg/kg/d completely inhibited tumor growth without any adverse effects in Balb/c-nu/nu mice xenograft Bcr-Abl–positive KU812 cells, at least 10-fold more potent than imatinib. Bafetinib at dose of 60, 120 and 200mg/kg significantly prolonged the survival of the mice in a dose-dependent manner in Balb/c-nu/nu mice received BaF3/wt cells intravenously, while all mice treated with 400 mg/kg/d imatinib died by day 25[1].
作用机制 Bafetinib is an ATP non-competitive inhibitor.[2]
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

1.73mL

0.35mL

0.17mL

8.67mL

1.73mL

0.87mL

17.34mL

3.47mL

1.73mL
参考文献

[1]Kimura S, Naito H, et al. NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia. Blood. 2005;106(12):3948-54.

[2]Kimura S, Ashihara E, Maekawa T. New tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia. Curr Pharm Biotechnol. 2006;7(5):371-9.

[3]WO2014039742A1

[4]Kantarjian H, le Coutre P, et al. Phase 1 study of INNO-406, a dual Abl/Lyn kinase inhibitor, in Philadelphia chromosome-positive leukemias after imatinib resistance or intolerance. Cancer. 2010;116(11):2665-72.