Preclinical activity of a novel CRM1 inhibitor in acute myeloid leukemia

摘要: Chromosome maintenance protein 1 (CRM1) is a nuclear export receptor involved in the active transport of tumor suppressors (e.g., p53 and nucleophosmin) whose function altered cancer because increased expression overactive transport. Blocking CRM1-mediated such proteins novel therapeutic strategy to restore suppressor function. Orally bioavailable selective inhibitors (SINE) that irreversibly bind CRM1 block this have been recently developed. Here we investigated antileukemic activity KPT-SINE (KPT-185 KPT-276) vitro vivo acute myeloid leukemia (AML). KPT-185 displayed potent antiproliferative properties at submicromolar concentrations (IC50 values; 100-500 nM), induced apoptosis (average 5-fold increase), cell-cycle arrest, differentiation AML cell lines patient blasts. A strong down-regulation oncogene FLT3 after KPT treatment both FLT3-ITD wild-type was observed. Finally, using FLT3-ITD-positive MV4-11 xenograft murine model, show mice with oral KPT-276 (analog for studies) significantly prolongs survival leukemic (P < .01). In summary, are highly AML. The preclinical results reported here support clinical trials