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].
The purpose was to assess the responsiveness of Bafetinib compared to other TKIs using luciferase assay; results showed unique reactivity patterns.
Int J Mol Sci. 2023 Sep 8;24(18):13863.
SW620/Ad300 cells
3 µM
72 hours
Bafetinib significantly sensitized ABCB1 overexpressing MDR cells to their anticancer substrates and increased the intracellular accumulation of anticancer drugs, particularly doxorubicin and [3H]-paclitaxel in ABCB1 overexpressing cells.
Sci Rep. 2016 May 9;6:25694.
NCI-H460/MX20 cells
3 µM
72 hours
Bafetinib significantly decreased the IC50 values of mitoxantrone and SN-38 in HEK/ABCG2-R482, HEK/ABCG2-R482G and HEK/ABCG2-R482T cells in a concentration dependent pattern.
Sci Rep. 2016 May 9;6:25694.
HEK293
2.138 µM
To assess intracellular engagement and inhibition of BRAF activity.
Cell Chem Biol. 2023 Nov 16;30(11):1478-1487.e7.
Bafetinib/巴氟替尼 动物研究
Dose
Mice: min = 0.2 mg/kg, max = 20 mg/kg[1] (p.o.); 4 mg/kgWO2014039742A1 (i.p.)
Rats: 30 mg/kg[4] (p.o.)
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