In vivo antiproliferative effect of NS-187, a dual Bcr-Abl/Lyn tyrosine kinase inhibitor, on leukemic cells harbouring Abl kinase domain mutations

Advanced-phase chronic myeloid leukemia patients treated with imatinib often relapse due to point mutations in the Ab1 kinase domain. We herein examine the in vitro and in vivo effects of a Ber-Abl/Lyn dual tyrosine kinase inhibitor, NS-187, on seven mutated Bcr-Ab1 proteins. NS-187 inhibited both Tyr393-phosphorylated and Tyr393-unphosphorylated Ab1, resulting in significant in vitro growth inhibition of cells expressing six of seven mutated Bcr-Ab1 kinases, though not T315I. Furthermore, NS-187 prolonged the survival of mice injected with leukemic cells expressing all mutated Bcr-Ab1 tested except T315I, and its efficacy correlated well with its in vitro effects. (c) 2006 Elsevier Ltd. All rights reserved.