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Title: The small molecule tyrosine kinase inhibitor AMN107 inhibits TEL-PDGFRbeta and FIP1L1-PDGFRalpha in vitro and in vivo
Authors: Stover, Elizabeth H
Chen, Jing
Lee, Benjamin H
Cools, Jan
McDowell, Elizabeth
Adelsperger, Jennifer
Cullen, Dana
Coburn, Allison
Moore, Sandra A
Okabe, Rachel
Fabbro, Doriano
Manley, Paul W
Griffin, James D
Gilliland, D Gary # ×
Issue Date: Nov-2005
Publisher: W.B. Saunders
Series Title: Blood vol:106 issue:9 pages:3206-3213
Abstract: AMN107 is a small molecule tyrosine kinase inhibitor developed, in the first instance, as a potent inhibitor of breakpoint cluster region-abelson (BCR-ABL). We tested its effectiveness against fusion tyrosine kinases TEL-platelet-derived growth factor receptorbeta (TEL-PDGFRbeta) and FIP1-like-1 (FIP1L1)-PDGFRalpha, which cause chronic myelomonocytic leukemia and hypereosinophilic syndrome, respectively. In vitro, AMN107 inhibited proliferation of Ba/F3 cells transformed by both TEL-PDGFRbeta and FIP1L1-PDGFRalpha with IC50 (inhibitory concentration 50%) values less than 25 nM and inhibited phosphorylation of the fusion kinases and their downstream signaling targets. The imatinib mesylate-resistant mutant TEL-PDGFRbeta T681I was sensitive to AMN107, whereas the analogous mutation in FIP1L1-PDGFRalpha, T674I, was resistant. In an in vivo bone marrow transplantation assay, AMN107 effectively treated myeloproliferative disease induced by TEL-PDGFRbeta and FIP1L1-PDGFRalpha, significantly increasing survival and disease latency and reducing disease severity as assessed by histopathology and flow cytometry. In summary, AMN107 can inhibit myeloid proliferation driven by TEL-PDGFRbeta and FIP1L1-PDGFRalpha and may be a useful drug for treatment of patients with myeloproliferative disease who harbor these kinase fusions.
URI: 
ISSN: 0006-4971
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Genetics Section (-)
Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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