1.Selective FLT3 inhibitor FI-700 neutralizes Mcl-1 and enhances p53-mediated apoptosis in AML cells with activating mutations of FLT3 through Mcl-1/Noxa axis.
Kojima K1, Konopleva M, Tsao T, Andreeff M, Ishida H, Shiotsu Y, Jin L, Tabe Y, Nakakuma H. Leukemia. 2010 Jan;24(1):33-43. doi: 10.1038/leu.2009.212. Epub 2009 Oct 15.
Treatment using Fms-like tyrosine kinase-3 (FLT3) inhibitors is a promising approach to overcome the dismal prognosis of acute myeloid leukemia (AML) with activating FLT3 mutations. Current trials are combining FLT3 inhibitors with p53-activating conventional chemotherapy. The mechanisms of cytotoxicity of FLT3 inhibitors are poorly understood. We investigated the interaction of FLT3 and p53 pathways after their simultaneous blockade using the selective FLT3 inhibitor FI-700 and the MDM2 inhibitor Nutlin-3 in AML. We found that FI-700 immediately reduced antiapoptotic Mcl-1 levels and enhanced Nutlin-induced p53-mediated mitochondrial apoptosis in FLT3/internal tandem duplication cells through the Mcl-1/Noxa axis. FI-700 induced proteasome-mediated degradation of Mcl-1, resulting in the reduced ability of Mcl-1 to sequester proapoptotic Bim. Nutlin-3 induced Noxa, which displaced Bim from Mcl-1. The FI-700/Nutlin-3 combination profoundly activated Bax and induced apoptosis.
2.A novel FLT3 inhibitor FI-700 selectively suppresses the growth of leukemia cells with FLT3 mutations.
Kiyoi H1, Shiotsu Y, Ozeki K, Yamaji S, Kosugi H, Umehara H, Shimizu M, Arai H, Ishii K, Akinaga S, Naoe T. Clin Cancer Res. 2007 Aug 1;13(15 Pt 1):4575-82.
PURPOSE: The aim of this study was to evaluate the antileukemia activity of a novel FLT3 kinase inhibitor, FI-700.