The Bcr-Abl tyrosine kinase inhibitor imatinib and promising new agents against Philadelphia chromosome-positive leukemias

Chronic myeloid leukemia (CML) was the first human malignant disease to be linked to a single, acquired genetic abnormality. Identification of the Bcr-Abl kinase fusion protein and its pivotal role in the pathogenesis of CML provided new opportunities to develop molecular-targeted therapies. Imatinib mesylate (IM, Gleevec, Novartis Pharmaceuticals, Basel, Switzerland), which specifically inhibits the autophosphorylation of the Abl TK, has improved the treatment of CML. However, resistance is often reported in patients with advanced-stage disease. Several novel TK inhibitors have been developed that override IM resistance mechanisms caused by point mutations within the Abl kinase domain. Inhibitors of AN TK are divided into two main groups, namely, ATP-competitive and ATP noncompetitive inhibitors. The ATP-competitive inhibitors fall into two subclasses, the Src/Abl inhibitors, and the 2-phenylaminopyrimidine-based compounds. Dasatinib (formerly BMS-354825), AP23464, SKI-606, and PD166326 are classified as Src/Abl inhibitors, while nilotinib (AMN107) and INNO-406 (NS-187) belong to the latter subclass of inhibitors. Of these agents, dasatinib and nilotinib underwent clinical trials earlier than the others and favorable results are now accumulating. Clinical studies of the other compounds, including SKI-606 and INNO-406, have been performed in rapid succession. Because of their strong affinities for the ATP-binding site compared to IM, most ATP-competitive inhibitors may be effective in IM-resistant patients. However, an ATP-competitive inhibitor that can inhibit the phosphorylation of T315I Bcr-Abl has not yet been developed. Instead, ATP noncompetitive inhibitors, such as ON012380, Aurora kinase inhibitor MK0457 (VX-680), and p38 MAP kinase inhibitor BIRB-796, have been developed to address this problem. This review provides an update on the underlying pathophysiologies of disease progression and IM resistance, and discusses the development of new targeted TK inhibitors for managing CML and the importance of future strategies targeting CML stem cells.