title: 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: Division of Hematology, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115, USA.
authors: Elizabeth H
authors: EH
authors: Stover
authors: Jing
authors: J
authors: Chen
authors: Benjamin H
authors: BH
authors: Lee
authors: Jan
authors: J
authors: Cools
authors: Elizabeth
authors: E
authors: McDowell
authors: Jennifer
authors: J
authors: Adelsperger
authors: Dana
authors: D
authors: Cullen
authors: Allison
authors: A
authors: Coburn
authors: Sandra A
authors: SA
authors: Moore
authors: Rachel
authors: R
authors: Okabe
authors: Doriano
authors: D
authors: Fabbro
authors: Paul W
authors: PW
authors: Manley
authors: James D
authors: JD
authors: Griffin
authors: D Gary
authors: DG
authors: Gilliland
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002460:Cell Line; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics; D009196:Myeloproliferative Disorders / Q000378:metabolism / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate; D039221:mRNA Cleavage and Polyadenylation Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
chemical_list: D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C120888:TEL-PDGFRbeta fusion protein, human; D039221:mRNA Cleavage and Polyadenylation Factors; C479819:FIP1L1-PDGFRA fusion protein, human; D020796:Receptor, Platelet-Derived Growth Factor alpha; C498826:nilotinib