title: KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation.
abstract: KW-2449, a multikinase inhibitor of FLT3, ABL, ABL-T315I, and Aurora kinase, is under investigation to treat leukemia patients. In this study, we examined its possible modes of action for antileukemic effects on FLT3-activated, FLT3 wild-type, or imatinib-resistant leukemia cells. KW-2449 showed the potent growth inhibitory effects on leukemia cells with FLT3 mutations by inhibition of the FLT3 kinase, resulting in the down-regulation of phosphorylated-FLT3/STAT5, G(1) arrest, and apoptosis. Oral administration of KW-2449 showed dose-dependent and significant tumor growth inhibition in FLT3-mutated xenograft model with minimum bone marrow suppression. In FLT3 wild-type human leukemia, it induced the reduction of phosphorylated histone H3, G(2)/M arrest, and apoptosis. In imatinib-resistant leukemia, KW-2449 contributed to release of the resistance by the simultaneous down-regulation of BCR/ABL and Aurora kinases. Furthermore, the antiproliferative activity of KW-2449 was confirmed in primary samples from AML and imatinib-resistant patients. The inhibitory activity of KW-2449 is not affected by the presence of human plasma protein, such as alpha1-acid glycoprotein. These results indicate KW-2449 has potent growth inhibitory activity against various types of leukemia by several mechanisms of action. Our studies indicate KW-2449 has significant activity and warrants clinical study in leukemia patients with FLT3 mutations as well as imatinib-resistant mutations.
authors.affiliation: Fuji Research Park, Kyowa Hakko Kirin, Shizuoka, Japan. yukimasa.shiotsu@kyowa-kirin.co.jp
authors.forename: Yukimasa
authors.initials: Y
authors.lastname: Shiotsu
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kiyoi
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ishikawa
authors.forename: Ryohei
authors.initials: R
authors.lastname: Tanizaki
authors.forename: Makiko
authors.initials: M
authors.lastname: Shimizu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Umehara
authors.forename: Kenichi
authors.initials: K
authors.lastname: Ishii
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Mori
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ozeki
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Minami
authors.forename: Akihiro
authors.initials: A
authors.lastname: Abe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maeda
authors.forename: Tadakazu
authors.initials: T
authors.lastname: Akiyama
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kanda
authors.forename: Yuko
authors.initials: Y
authors.lastname: Sato
authors.forename: Shiro
authors.initials: S
authors.lastname: Akinaga
authors.forename: Tomoki
authors.initials: T
authors.lastname: Naoe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D018922:HL-60 Cells; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D007532:Isoleucine / Q000235:genetics; D020014:K562 Cells; D007938:Leukemia / Q000235:genetics* / Q000473:pathology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D016513:Mice, SCID; D020125:Mutation, Missense / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051562:Proto-Oncogene Proteins c-bcr / Q000235:genetics; D013912:Threonine / Q000235:genetics; D014178:Translocation, Genetic / Q000235:genetics; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D007191:Indazoles; C543891:KW 2449; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D007532:Isoleucine; D013912:Threonine; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D016044:Fusion Proteins, bcr-abl; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr