The small molecule tyrosine kinase inhibitor AMN107 inhibits TEL-PDGFR and FIP1L1-PDGFR 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 receptorβ (TEL-PDGFRβ) and FIP1-like-1 (FIP1L1)–PDGFRα, which cause chronic myelomonocytic leukemia and hypereosinophilic syndrome, respectively. In vitro, AMN107 inhibited proliferation of Ba/F3 cells transformed by both TEL-PDGFRβ and FIP1L1-PDGFRα 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-PDGFRβ T681I was sensitive to AMN107, whereas the analogous mutation in FIP1L1-PDGFRα, T674I, was resistant. In an in vivo bone marrow transplantation assay, AMN107 effectively treated myeloproliferative disease induced by TEL-PDGFRβ and FIP1L1-PDGFRα, 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-PDGFRβ and FIP1L1-PDGFRα and may be a useful drug for treatment of patients with myeloproliferative disease who harbor these kinase fusions.