New tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia

Imatinib mesylate, Ab1 tyrosine kinase inhibitor, has improved the treatment of Bcr-Ab1-positive leukemia such as chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph(+)ALL). However, resistance is often reported in patients with advanced-stage disease. Several novel tyrosine kinase inhibitors, which have been developed to override imatinib resistance mechanisms such as overexpression of Bcr-Ab1 and point mutations within the Ab1 kinase domain, are currently competing. Inhibitors of Ab1 tyrosine kinase are divided into two main groups, namely, ATP-competitive and ATP non-competitive inhibitors. Moreover, ATP-competitive inhibitors are fall into two subclasses, i.e. the Src/Ab1 inhibitors, and 2-phenylaminopyrimidin-based compounds. Dasatinib (formerly BMS-354825), AP23464, SKI-606 and PD166326 are classified as Src/Ab1 inhibitors while AMN107 and NS-187 (INNO-406) belong to the latter subclass of inhibitors. Among these agents, clinical studies on dasatinib and AMN107 had started earlier than the others and favorable results are accumulating. Clinical studies of other compounds including NS-187 (INNO-406) will be performed in rapid succession. Because of its strong affinity, most ATP competitive inhibitors may be effective against imatinib-resistant patients. However, to date, an ATP-competitive inhibitor that can inhibit the phosphorylation of T315I Bcr-Ab1 has not yet been developed. To address this problem, ATP non-competitive inhibitors such as ON012380, Aurora kinase inhibitor VX-680 and p38 MAP kinase inhibitor BIRB-796 have been developed. It may be necessary-for the improvement of CML and WALL treatment to be taken into consideration of the combination therapy with novel ATP-competitive inhibitors and these agents.