KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation.
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.
Shiotsu
Yukimasa
Y
Fuji Research Park, Kyowa Hakko Kirin, Shizuoka, Japan. yukimasa.shiotsu@kyowa-kirin.co.jp
Kiyoi
Hitoshi
H
Ishikawa
Yuichi
Y
Tanizaki
Ryohei
R
Shimizu
Makiko
M
Umehara
Hiroshi
H
Ishii
Kenichi
K
Mori
Yumiko
Y
Ozeki
Kazutaka
K
Minami
Yosuke
Y
Abe
Akihiro
A
Maeda
Hiroshi
H
Akiyama
Tadakazu
T
Kanda
Yutaka
Y
Sato
Yuko
Y
Akinaga
Shiro
S
Naoe
Tomoki
T
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*
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