ABSTRACT
Several strategies are being investigated in order to overcome imatinib resistance, including the development of novel tyrosine kinase inhibitors with enhanced activity against breakpoint cluster region-Abl compared to imatinib. Adenosine triphosphate-competitive compounds originally developed as Src inhibitors frequently have potent inhibition of Abl kinase due to the striking resemblance between the catalytically active state of both protein kinases. Pharmacokinetics in a rat model identified a high volume of distribution for dasatinib with systemic clearance of approximately 40% of hepatic blood flow. Notably, dasatinib markedly inhibited the growth of bone marrow progenitors isolated from patients with chronic myeloid leukemia (CML) with imatinib-sensitive or -resistant disease, but not marrow progenitors obtained from healthy volunteers. Most patients treated with imatinib have minimal residual disease as detected by polymerase chain reaction. Despite the excellent results obtained with imatinib, there is still a clear need to improve therapy in CML.
