Effects of MLN518, a dual FLT3 and KIT inhibitor, on normal and malignant hematopoiesis.

Blood
Ian J GriswoldMichael W N Deininger

Abstract

Internal tandem duplications (ITDs) of the FMS-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase are found in approximately 30% of patients with acute myelogenous leukemia (AML) and are associated with a poor prognosis. FLT3 ITD mutations result in constitutive kinase activation and are thought to be pathogenetically relevant, implicating FLT3 as a plausible therapeutic target. MLN518 (formerly CT53518) is a small molecule inhibitor of the FLT3, KIT, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases with significant activity in murine models of FLT3 ITD-positive leukemia. Given the importance of FLT3 and KIT for normal hematopoietic progenitor cells, we analyzed the effect of MLN518 on murine hematopoiesis under steady-state conditions, after chemotherapy-induced myelosuppression, and during bone marrow transplantation. In these assays, we show that MLN518 has mild toxicity toward normal hematopoiesis at concentrations that are effective in treating FLT3 ITD-positive leukemia in mice. We also demonstrate that MLN518 preferentially inhibits the growth of blast colonies from FLT3 ITD-positive compared with ITD-negative patients with AML, at concentrations that do not significantly affect colony formation b...Continue Reading

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Citations

Jan 20, 2011·Current Opinion in Hematology·Amir Fathi, Mark Levis
Dec 8, 2011·Journal of Pediatric Hematology/oncology·Sachiko Ohshima-HosoyamaCharles Keller
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Mar 7, 2021·International Journal of Molecular Sciences·Manali TilakNina Jones

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