1. Academic Validation
  2. KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation

KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation

  • Blood. 2009 Aug 20;114(8):1607-17. doi: 10.1182/blood-2009-01-199307.
Yukimasa Shiotsu 1 Hitoshi Kiyoi Yuichi Ishikawa Ryohei Tanizaki Makiko Shimizu Hiroshi Umehara Kenichi Ishii Yumiko Mori Kazutaka Ozeki Yosuke Minami Akihiro Abe Hiroshi Maeda Tadakazu Akiyama Yutaka Kanda Yuko Sato Shiro Akinaga Tomoki Naoe
Affiliations

Affiliation

  • 1 Fuji Research Park, Kyowa Hakko Kirin, Shizuoka, Japan. yukimasa.shiotsu@kyowa-kirin.co.jp
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.

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