New tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia.

Imatinib mesylate, Abl tyrosine kinase inhibitor, has improved the treatment of Bcr-Abl-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-Abl and point mutations within the Abl kinase domain, are currently competing. Inhibitors of Abl 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/Abl inhibitors, and 2-phenylaminopyrimidin-based compounds. Dasatinib (formerly BMS-354825), AP23464, SKI-606 and PD166326 are classified as Src/Abl 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-Abl 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 Ph(+)ALL treatment to be taken into consideration of the combination therapy with novel ATP-competitive inhibitors and these agents.