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

Shiotsu, Yukimasa; Kiyoi, Hitoshi; Ishikawa, Yuichi; Tanizaki, Ryohei; Shimizu, Makiko; Umehara, Hiroshi; Ishii, Kenichi; Mori, Yumiko; Ozeki, Kazutaka; Minami, Yosuke; Abe, Akihiro; Maéda, Hiroshi; Akiyama, Tadakazu; Kanda, Yutaka; Sato, Yuko; Akinaga, Shiro; Naoe, Tomoki

doi:10.1182/blood-2009-01-199307

Cited by 112 publications

(84 citation statements)

References 34 publications

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“…139 Preclinical data also suggested activity against CD34 þ CML progenitor cells from previously untreated patients, as well as from those derived from imatinib-resistant KW-2449 (Kyowa Hakko Kirin Pharma, Tokyo, Japan) KW-2449 is also an orally bioavailable Aurora kinase A and B inhibitor with concurrent nanomolar range activity against Abl, including the T315I, Flt3 and FGFR1. 143,144 In a phase I study, KW-2449 was administered between 25-500 mg/day utilizing a twice-daily dosing scheme for 14-days with a 7-28 days rest period. Five imatinib-resistant CML patients were evaluated, three of whom carried the T315I mutation.…”

Section: Aurora Kinase Inhibitorsmentioning

confidence: 99%

Seeking the causes and solutions to imatinib-resistance in chronic myeloid leukemia

2010

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Although only 5000 new cases of chronic myeloid leukemia (CML) were seen in the United States in 2009, this neoplasm continues to make scientific headlines year-after-year. Advances in understanding the molecular pathogenesis coupled with exciting developments in both drug design and development, targeting the initiating tyrosine kinase, have kept CML in the scientific limelight for more than a decade. Indeed, imatinib, a small-molecule inhibitor of the leukemia-initiating Bcr-Abl tyrosine kinase, has quickly become the therapeutic standard for newly diagnosed chronic phase-CML (CP-CML) patients. Yet, nearly one-third of patients will still have an inferior response to imatinib, either failing to respond to primary therapy or demonstrating progression after an initial response. Significant efforts geared toward understanding the molecular mechanisms of imatinib resistance have yielded valuable insights into the cellular biology of drug trafficking, enzyme structure and function, and the rational design of novel small molecule enzyme inhibitors. Indeed, new classes of kinase inhibitors have recently been investigated in imatinibresistant CML. Understanding the pathogenesis of tyrosine kinase inhibitor resistance and the molecular rationale for the development of second and now third generation therapies for patients with CML will be keys to further disease control over the next 10 years.

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Section: Aurora Kinase Inhibitorsmentioning

confidence: 99%

Seeking the causes and solutions to imatinib-resistance in chronic myeloid leukemia

2010

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“…Investigated in Phase I and II clinical trials for AML patients that are not candidates for approved therapy is KW-2449 (Pratz and Levis, 2008;Pratz et al, 2009;Shiotsu et al, 2009), for the purpose of determining its maximum tolerated dose. In a Phase I trial, KW-2449 treatment led to transient decreases in peripheral blast counts (Cortes et al, 2008;Pratz and Levis, 2008;Pratz et al, 2009 (Fiedler et al, 2005;Kancha et al, 2007;O'Farrell et al, 2003a, b), as well as the piperazinyl quinazoline MLN518 (tandutinib; CT53518; Millennium, Cambridge, MA, USA) (Kelly et al, 2002b;Cheng and Paz, 2008).…”

Section: Kinase Inhibitors Under Clinical Investigation For Mutant Flmentioning

confidence: 99%

Drug resistance in mutant FLT3-positive AML

et al. 2010

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Mutant Fms-Like Tyrosine kinase-3 (FLT3), which is expressed in the leukemic cells of a subpopulation of acute myeloid leukemia (AML) patients, represents an attractive target for the therapy of AML. There are several FLT3 inhibitors presently in clinical trials with sufficient efficacy and toxicity features to warrant further testing in combination with standard therapies. However, the transient and partial responses observed in AML patients treated with FLT3 inhibitors, coupled with the discovery of drug-resistant leukemic blast cells in AML patients, have made resistance to FLT3 inhibitors a growing concern. In this study, we provide an overview of the role of mutant FLT3 in AML, FLT3 inhibitors under clinical and preclinical investigation, mechanisms of resistance to FLT3 inhibitors, and possible therapeutic approaches to overcoming this resistance.

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Section: Mechanism Of Abl Inhibitionmentioning

confidence: 99%

“…43 Pre-clinical studies demonstrated the activity of KW-2449 against the AML cell lines (MOLM-13 and MV-4-11), reducing phosphorylated FLT3 and STAT5. 43 Both these cell lines harbor internal tandem duplications of FLT3 (FLT3-ITD). 44 Furthermore, FLT3 wild-type cells (RS-4-11) were sensitive to KW-2449, consistent with the activity by inhibition of Aurora kinases as demonstrated by reduced phosphorylation of histone H3, G2/M arrest and apoptosis.…”

Section: Mechanism Of Abl Inhibitionmentioning

confidence: 99%

“…The extent of Aurora inhibition in the MOLM-13 cells and FLT3 inhibition in the RS-4-11 cells was not reported. 43 Of great interest are the recent results of a phase I trial of KW-2449 in AML patients, which used the plasma inhibitory activity assay to monitor ex vivo inhibition of FLT3 as a secondary end point. 45 Data from preclinical studies have shown that continuous exposure to FLT3 inhibitors at concentrations sufficient to continually abrogate FLT3 autophosphorylation to 10-20% of baseline is required for cytotoxicity.…”

Section: Mechanism Of Abl Inhibitionmentioning

confidence: 99%

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Aurora kinase inhibitors: novel small molecules with promising activity in acute myeloid and Philadelphia-positive leukemias

et al. 2010

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

Cited by 112 publications

References 34 publications

Seeking the causes and solutions to imatinib-resistance in chronic myeloid leukemia

Seeking the causes and solutions to imatinib-resistance in chronic myeloid leukemia

Drug resistance in mutant FLT3-positive AML

Aurora kinase inhibitors: novel small molecules with promising activity in acute myeloid and Philadelphia-positive leukemias

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