kw-2449 and Leukemia

Topics: Acute Disease; Clinical Trials as Topic; Drug Design; Enzyme Inhibitors; fms-Like Tyrosine Kinase 3; Humans; Indazoles; Leukemia; Mutation; Piperazines; Quinazolines; Signal Transduction; Staurosporine

KW-2449, a multikinase inhibitor of FLT3, ABL, ABL-T315I, and Aurora kinase, is under investigation to treat leukemia patients. In this study, we examined its possible modes of action for antileukemic effects on FLT3-activated, FLT3 wild-type, or imatinib-resistant leukemia cells. KW-2449 showed the potent growth inhibitory effects on leukemia cells with FLT3 mutations by inhibition of the FLT3 kinase, resulting in the down-regulation of phosphorylated-FLT3/STAT5, G(1) arrest, and apoptosis. Oral administration of KW-2449 showed dose-dependent and significant tumor growth inhibition in FLT3-mutated xenograft model with minimum bone marrow suppression. In FLT3 wild-type human leukemia, it induced the reduction of phosphorylated histone H3, G(2)/M arrest, and apoptosis. In imatinib-resistant leukemia, KW-2449 contributed to release of the resistance by the simultaneous down-regulation of BCR/ABL and Aurora kinases. Furthermore, the antiproliferative activity of KW-2449 was confirmed in primary samples from AML and imatinib-resistant patients. The inhibitory activity of KW-2449 is not affected by the presence of human plasma protein, such as alpha1-acid glycoprotein. These results indicate KW-2449 has potent growth inhibitory activity against various types of leukemia by several mechanisms of action. Our studies indicate KW-2449 has significant activity and warrants clinical study in leukemia patients with FLT3 mutations as well as imatinib-resistant mutations.

Topics: Animals; Antineoplastic Agents; Cell Proliferation; Cells, Cultured; Drug Evaluation, Preclinical; fms-Like Tyrosine Kinase 3; Fusion Proteins, bcr-abl; HL-60 Cells; Humans; Indazoles; Isoleucine; K562 Cells; Leukemia; Male; Mice; Mice, Inbred C3H; Mice, SCID; Mutation, Missense; Piperazines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcr; Threonine; Translocation, Genetic