The small molecule tyrosine kinase inhibitor AMN107 inhibits TEL-PDGFRbeta and FIP1L1-PDGFRalpha in vitro and in vivo.

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.

• Authors: Elizabeth H Stover, Jing Chen, Benjamin H Lee, Jan Cools, Elizabeth McDowell, Jennifer Adelsperger, Dana Cullen, Allison Coburn, Sandra A Moore, Rachel Okabe, Doriano Fabbro, Paul W Manley, James D Griffin, D Gary Gilliland
• Journal: Blood (Blood) Vol. 106 Issue 9 Pg. 3206-13 (Nov 01 2005) ISSN: 0006-4971 [Print] United States
• PMID: 16030188 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Oncogene Proteins, Fusion
• Protein Kinase Inhibitors
• Pyrimidines
• TEL-PDGFRbeta fusion protein, human
• mRNA Cleavage and Polyadenylation Factors
• FIP1L1-PDGFRA fusion protein, human
• Receptor, Platelet-Derived Growth Factor alpha
• nilotinib

Topics

• Animals
• Bone Marrow Transplantation
• Cell Line
• Disease Models, Animal
• Humans
• Mice
• Mutation (genetics)
• Myeloproliferative Disorders (metabolism, pathology)
• Oncogene Proteins, Fusion (antagonists & inhibitors, genetics, metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Pyrimidines (pharmacology)
• Receptor, Platelet-Derived Growth Factor alpha (antagonists & inhibitors, genetics, metabolism)
• Survival Rate
• mRNA Cleavage and Polyadenylation Factors (antagonists & inhibitors, genetics, metabolism)