Author/Authors :
Kelly، نويسنده , , Louise M and Yu، نويسنده , , Jin-Chen and Boulton، نويسنده , , Christina L and Apatira، نويسنده , , Mutiah and Li، نويسنده , , Jason and Sullivan، نويسنده , , Carol M and Williams، نويسنده , , Ifor and Amaral، نويسنده , , Sonia M and Curley، نويسنده , , David P and Duclos، نويسنده , , Nicole and Neuberg، نويسنده , , Donna Moxley Scarborough، نويسنده , , Robert M and Pandey، نويسنده , , Anjali and Hollenbach، نويسنده , , Stanley and Abe، نويسنده , , Keith and Lokker، نويسنده , , Nathalie A and Gilliland، نويسنده , , D.Gary and Giese، نويسنده , , Neill A، نويسنده ,
Abstract :
Up to 30% of acute myelogenous leukemia (AML) patients harbor an activating internal tandem duplication (ITD) within the juxtamembrane domain of the FLT3 receptor, suggesting that it may be a target for kinase inhibitor therapy. For this purpose we have developed CT53518, a potent antagonist that inhibits FLT3, platelet-derived growth factor receptor (PDGFR), and c-Kit (IC50 ∼200 nM), while other tyrosine or serine/threonine kinases were not significantly inhibited. In Ba/F3 cells expressing different FLT3-ITD mutants, CT53518 inhibited IL-3-independent cell growth and FLT3-ITD autophosphorylation with an IC50 of 10–100 nM. In human FLT3-ITD-positive AML cell lines, CT53518 induced apoptosis and inhibited FLT3-ITD phosphorylation, cellular proliferation, and signaling through the MAP kinase and PI3 kinase pathways. Therapeutic efficacy of CT53518 was demonstrated both in a nude mouse model and in a murine bone marrow transplant model of FLT3-ITD-induced disease.
