The kinase inhibitor LS104 induces apoptosis, enhances cytotoxic effects of chemotherapeutic drugs and is targeting the receptor tyrosine kinase FLT3 in acute myeloid leukemia

  • Leuk Res. 2008 Nov;32(11):1698-708. doi: 10.1016/j.leukres.2008.05.003.
Stefan Kasper  1 ,  Frank Breitenbuecher ,  Yvette Hoehn ,  Florian Heidel ,  Daniel B Lipka ,  Boyka Markova ,  Christoph Huber ,  Thomas Kindler ,  Thomas Fischer
Affiliations
  • 1. 3rd Medical Department, Johannes-Gutenberg University of Mainz, Mainz, Germany.
PMID: 18556063 DOI: 10.1016/j.leukres.2008.05.003
Abstract

Activating mutations of FLT3 are found in approximately one-third of acute myeloid leukemia (AML)-cases and are considered to represent an attractive therapeutic target. In this study, we report that the hydroxystyryl-acrylonitrile compound LS104 inhibits proliferation and induces potent cytotoxic effects in FLT3 expressing leukemic cells in vitro. Immunoblot and phosphoprotein-FACS analysis demonstrated inhibiton of phosphorylation of FLT3-ITD and of its downstream targets. In pharmacokinetic studies, a rapid and dose dependent cellular uptake of LS104 lasting up to 11h could be demonstrated. Combination of LS104 with chemotherapeutic agents markedly enhanced cytotoxic effects. Recently, a phase I clinical trial investigating LS104 in refractory/relapsed hematologic malignancies has been initiated.

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