A Bcr-Abl inhibitor
Bcr-Abl, a fusion protein with deregulated tyrosine kinase activity, is highly expressed in chronic myelogenous leukemia (CML). Bafetinib is a rationally developed tyrosine kinase inhibitor based on the chemical structure of imatinib , with modifications added to improve binding and potency against Bcr-Abl kinase (IC50 = 5.8 nM).1 It is 25- to 55-fold more potent than imatinib in vitro and ≥10-fold more potent in vivo.1 Bafetinib inhibits 12 out of the 13 most frequent imatinib-resistant Bcr-Abl point mutations, but not the T315I mutation and also targets the Src family kinase Lyn (IC50 = 19 nM), which has been associated with resistance to imatinib in CML.1
1.Kimura, S., Naito, H., Segawa, H., et al.NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemiaBlood106(12)3948-3954(2005)
| Kinase experiment [1]: | |
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Kinase assays |
Bcr-Abl kinase assays were performed in 25 μL of reaction mixture containing 250 μM peptide substrate, 740 Bq/μL [γ-33P]ATP, and 20 μM cold adenosine triphosphate (ATP) by using the SignaTECT protein tyrosine kinase assay system. Each Bcr-Abl kinase was used at a concentration of 10 nM. Kinase assays for Abl, Src, and Lyn were carried out with an enzyme-linked immunosorbent assay (ELISA) kit from Carna Biosciences. |
| Cell experiment [1]: | |
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Cell lines |
K562, BaF3/wt and KU812 cell lines |
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Preparation method |
The solubility of this compound in DMSO is > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
0-10 μM for 3 days |
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Applications |
Bafetinib could suppress the growth of the Bcr-Abl–positive cell lines K562, KU812, and BaF3/wt. |
| Animal experiment [1]: | |
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Animal models |
Bcr-Abl–positive KU812 mouse model |
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Dosage form |
0.2 mg/kg/d and 20 mg/kg/d orally twice a day for 26 consecutive days |
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Application |
Bafetinib suppressed the growth of Bcr-Abl–bearing tumors (KU812) and markedly extends the survival of mice bearing such tumors. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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参考文献: [1]. Kimura S, Naito H, Segawa 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): 3948-3954. |
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