title: Effects of AMN107, a novel aminopyrimidine tyrosine kinase inhibitor, on human mast cells bearing wild-type or mutated codon 816 c-kit.
abstract: Most adults with systemic mastocytosis (SM) carry an activating mutation in the codon 816 of c-kit. We investigated the activity of the new tyrosine kinase inhibitor AMN107 on c-kit mutated mast cell lines and bone marrow samples from patients with SM and compared it to that of imatinib mesylate, a tyrosine kinase inhibitor effective in some patients with SM. In HMC-1(560) mast cells carrying wild-type codon 816 c-kit, AMN107 was very effective and as potent as imatinib in inhibiting cellular proliferation and inducing apoptosis (P<0.0823). By contrast, in HMC-1(560,816) cells bearing a c-kit mutation in codon 816, neither drug exerted a significant effect (P<0.0015). AMN107 was also as effective as imatinib in inhibiting phosphorylation of c-kit in HMC-1(560) cells. However, AMN107 had little effect on ex vivo survival of bone marrow mast cells with 816 c-kit mutation obtained from patients with SM. Based upon our results, AMN107 and imatinib are equipotent against mast cells with wild-type c-kit and those harboring the juxtamembrane D560G c-kit mutant but have no significant activity over the dose range tested against cells expressing the c-kit D816V mutant tyrosine kinase.
authors.affiliation: Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Unit 428, 1515 Holcombe Blvd., Houston, TX 77030, United States. sverstov@mdanderson.org <sverstov@mdanderson.org>
authors.forename: Srdan
authors.initials: S
authors.lastname: Verstovsek
authors.forename: Cem
authors.initials: C
authors.lastname: Akin
authors.forename: Taghi
authors.initials: T
authors.lastname: Manshouri
authors.forename: Alfonso
authors.initials: A
authors.lastname: Quintás-Cardama
authors.forename: Ly
authors.initials: L
authors.lastname: Huynh
authors.forename: Paul
authors.initials: P
authors.lastname: Manley
authors.forename: Ayalew
authors.initials: A
authors.lastname: Tefferi
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Giles
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
mesh_terms: D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D000068877:Imatinib Mesylate; D008407:Mast Cells / Q000187:drug effects*; D034721:Mastocytosis, Systemic / Q000235:genetics*; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011743:Pyrimidines / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; C498826:nilotinib