The small molecule tyrosine kinase inhibitor AMN107 inhibits TEL-PDGFRβ and FIP1L1-PDGFRα in vitro and in vivo

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 receptor beta (TEL-PDGFR beta) and FlP1-like-1 (FIP1L1)-PDGFR alpha, which cause chronic myelomonocytic leukemia and hypereosinophilic syndrome, respectively. In vitro, AMN107 inhibited proliferation of Ba/F3 cells transformed by both TEL-PDGFR beta and FIP1L1-PDGFR alpha 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 TELPDGF beta T681l was sensitive to AMN107, whereas the analogous mutation in FIP1L1-PDGFR alpha, T6741, was resistant. In an in vivo bone marrow transplantation assay, AMN107 effectively treated myeloproliferative disease induced by TELPDGFR beta and FIP1L1-PDGFR alpha, 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-PDGFR beta and FIP1L1-PDGFR alpha and may be a useful drug for treatment of patients with myeloproliferative disease who harbor these kinase fusions.