Bafetinib is a potent and selective dual Bcr-Abl/Lyn inhibitor with IC50 of 5.8 nM/19 nM in cell-free assays, does not inhibit the phosphorylation of the T315I mutant and is less potent toPDGFR and c-Kit.
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].
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