Advances in the understanding of the molecular basis for acute myeloid leukemia 
(AML) have generated new potential targets for treatment. Fms-like tyrosine 
kinase 3 (FLT3) is one of the most frequently mutated genes in AML and mutations 
in this gene are associated with poor overall survival. AXL plays a role in the 
activation of FLT3 and has been implicated in the pathogenesis of AML. The 
studies reported here evaluated the ability of a novel FLT3/AXL inhibitor, 
gilteritinib, to block mutated FLT3 in cellular and animal models of AML. 
Initial kinase studies showed that gilteritinib, a type I tyrosine kinase 
inhibitor, was highly selective for both FLT3 and AXL while having weak activity 
against c-KIT. Gilteritinib demonstrated potent inhibitory activity against the 
internal tandem duplication (FLT3-ITD) and FLT3-D835Y point mutations in 
cellular assays using MV4-11 and MOLM-13 cells as well as Ba/F3 cells expressing 
mutated FLT3. Gilteritinib also inhibited FLT3-F691 mutations, although to a 
lesser degree, in these assays. Furthermore, gilteritinib decreased the 
phosphorylation levels of FLT3 and its downstream targets in both cellular and 
animal models. In vivo, gilteritinib was distributed at high levels in 
xenografted tumors after oral administration. The decreased FLT3 activity and 
high intratumor distribution of gilteritinib translated to tumor regression and 
improved survival in xenograft and intra-bone marrow transplantation models of 
FLT3-driven AML. No overt toxicity was seen in mouse models treated with 
gilteritinib. These results indicate that gilteritinib may be an important 
next-generation FLT3 inhibitor for use in the treatment of FLT3 
mutation-positive AML.