Gilteritinib, a FLT3/AXL inhibitor, shows antileukemic activity in mouse models of FLT3 mutated acute myeloid leukemia

Investigational New Drugs
Masamichi MoriSadao Kuromitsu

Abstract

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...Continue Reading

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Citations

Nov 23, 2017·Leukemia & Lymphoma·Mrinal M Patnaik
Feb 6, 2019·Drugs·Sohita Dhillon
Dec 7, 2018·Hematology·Rachel E Rau, Mignon L Loh
Apr 19, 2019·Leukemia & Lymphoma·Kiran Naqvi, Farhad Ravandi
Oct 31, 2019·The New England Journal of Medicine·Alexander E PerlMark J Levis
Jun 21, 2019·Current Topics in Medicinal Chemistry·Zhi-Gang SunYong Qian
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Methods Mentioned

BETA
xenograft
Assay
immunoprecipitation
ELISA

Software Mentioned

Protonate3D
MOE
SAS
GraphPad Prism
Excel
Maestro
WinNonlin
GLIDE

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