title: Sensitivity of human cells bearing oncogenic mutant kit isoforms to the novel tyrosine kinase inhibitor INNO-406.
abstract: The activity of the novel tyrosine kinase inhibitor INNO-406 against human cells with mutated KIT was investigated. Human mast cell (HMC)-1.1 cells with juxtamembrane domain mutation V560G, and HMC-1.2 cells with both V560G and the kinase domain mutation D816V, were treated with INNO-406 (0.02-5.00 microM) or imatinib for 72 h. INNO-406 and imatinib were equipotent against HMC-1 cells regarding cell proliferation (IC50 51 nM and 75 nM, respectively), inhibition of KIT phosphorylation, and induction of apoptosis. In contrast, neither drug was effective against HMC-1.2 cells at the dose range tested. The present results suggest clinical potential for INNO-406 in KIT V560G-expressing malignancies.
authors.affiliation: Department of Leukemia, The University of Texas, Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Jingxuan
authors.initials: J
authors.lastname: Pan
authors.forename: Alfonso
authors.initials: A
authors.lastname: Quintás-Cardama
authors.forename: Taghi
authors.initials: T
authors.lastname: Manshouri
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Srdan
authors.initials: S
authors.lastname: Verstovsek
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D010879:Piperazines; D020033:Protein Isoforms; 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*
chemical_list: D001549:Benzamides; D010879:Piperazines; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; C506918:bafetinib