The kinase inhibitor LS104 induces apoptosis, enhances cytotoxic effects of chemotherapeutic drugs and is targeting the receptor tyrosine kinase FLT3 in acute myeloid leukemia.
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.
Kasper
Stefan
S
3rd Medical Department, Johannes-Gutenberg University of Mainz, Mainz, Germany.
Breitenbuecher
Frank
F
Hoehn
Yvette
Y
Heidel
Florian
F
Lipka
Daniel B
DB
Markova
Boyka
B
Huber
Christoph
C
Kindler
Thomas
T
Fischer
Thomas
T
D000181:Acrylonitrile / Q000031:analogs & derivatives* / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D003114:Colony-Forming Units Assay; D003561:Cytarabine / Q000008:administration & dosage; D003630:Daunorubicin / Q000008:administration & dosage; D004359:Drug Therapy, Combination; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D017354:Point Mutation; D015398:Signal Transduction / Q000187:drug effects; D013343:Styrenes / Q000494:pharmacology*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
C530802:2-(benzylaminocarbonyl)-3-(3,4-dihydroxystyryl)acrylonitrile; D013343:Styrenes; D003561:Cytarabine; C497970:FLT3 protein, human; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3; D000181:Acrylonitrile; D003630:Daunorubicin