SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo

FLT3 (fms-related tyrosine kinase/Flk2/ Stk-2) is a receptor tyrosine kinase (RTK) primarily expressed on hematopoietic cells. In blasts from acute myelogenous leukemia (AML) patients, 2 'classes of FLT3 activating mutations have been identified: internal tandem duplication (ITD) mutations in the juxtamembrane domain (25%-30% of patients) and point mutations in the kinase domain activation loop (7%-8% of patients). FLT3-ITD mutations are the most common molecular defect identified in AML and have been shown to be an independent prognostic factor for decreased survival. FLT3-ITD is therefore an attractive molecular target for therapy. SU11248 is a recently described selective inhibitor with selectivity for split kinase domain RTKs, including platelet-derived growth factor receptors, vascular endothelial growth,factor receptors, and KIT. We show that SU11248 Aldo has potent activity against Wild-type FLT3 ( FLT3-WT), FLT3-ITD, And FLT3 activation loop FLT3-Asp835) mutants in phosphorylation Assays. SU11246 inhibits FLT3-driven phosphorylation and induces apoptosis in vitro. In addition, SU11248 inhibits FLT3-induced VEGF production. The in vivo efficacy of SU11248 was investigated in 2 FLT3-ITD models: a subcutaneous tumor xenograft model and a bone marrow engraftment model. We show that SU11248 (20 mg/kg/d) dramatically regresses FLT3-ITD tumors in the subcutaneous tumor xenograft model And prolongs survival in the bone - marrow engraftment model: Pharmacokinetic and pharmacodynamic analysis in subcutaneous tumors showed that a single administration of an efficacious drug dose potently inhibits FLT3-ITD phosphorylation for up, to 16 hours following A single dose. These results suggest that further exploration of SU11248 activity in AML patients is warranted. (C) 2003 by The American Society of Hematology.