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

Stefan Kasper; Frank Breitenbuecher; Yvette Hoehn; Florian Heidel; Daniel B Lipka; Boyka Markova; Christoph Huber; Thomas Kindler; Thomas Fischer

doi:10.1016/j.leukres.2008.05.003

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. Epub 2008 Jun 16.

Authors

Stefan Kasper¹, Frank Breitenbuecher, Yvette Hoehn, Florian Heidel, Daniel B Lipka, Boyka Markova, Christoph Huber, Thomas Kindler, Thomas Fischer

Affiliation

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acrylonitrile / analogs & derivatives*
Acrylonitrile / pharmacology
Adult
Aged
Aged, 80 and over
Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Apoptosis / drug effects*
Blotting, Western
Bone Marrow / drug effects
Bone Marrow / metabolism
Cell Differentiation / drug effects
Cell Proliferation / drug effects*
Colony-Forming Units Assay
Cytarabine / administration & dosage
Daunorubicin / administration & dosage
Drug Therapy, Combination
Female
Fluorescent Antibody Technique
Humans
Leukemia, Myeloid, Acute / drug therapy*
Leukemia, Myeloid, Acute / metabolism
Leukemia, Myeloid, Acute / pathology
Male
Mice
Middle Aged
Point Mutation
Signal Transduction / drug effects
Styrenes / pharmacology*
Tissue Distribution
Tumor Cells, Cultured
fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
fms-Like Tyrosine Kinase 3 / genetics
fms-Like Tyrosine Kinase 3 / metabolism

Substances

2-(benzylaminocarbonyl)-3-(3,4-dihydroxystyryl)acrylonitrile
Styrenes
Cytarabine
FLT3 protein, human
Flt3 protein, mouse
fms-Like Tyrosine Kinase 3
Acrylonitrile
Daunorubicin