Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma
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- James G. Christensen
- 1Cancer Biology, Departments of
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- Helen Y. Zou
- 1Cancer Biology, Departments of
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- Maria E. Arango
- 1Cancer Biology, Departments of
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- Qiuhua Li
- 1Cancer Biology, Departments of
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- Joseph H. Lee
- 1Cancer Biology, Departments of
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- Scott R. McDonnell
- 1Cancer Biology, Departments of
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- Shinji Yamazaki
- 2Pharmacokinetics, Dynamics, and Metabolism;
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- Gordon R. Alton
- 3Biochemical Pharmacology; and
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- Barbara Mroczkowski
- 4Molecular Biology, Pfizer Global Research and Development, La Jolla Laboratories, La Jolla, California
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- Gerrit Los
- 1Cancer Biology, Departments of
Description
<jats:title>Abstract</jats:title> <jats:p>A t(2;5) chromosomal translocation resulting in expression of an oncogenic kinase fusion protein known as nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) has been implicated in the pathogenesis of anaplastic large-cell lymphoma (ALCL). PF-2341066 was recently identified as a p.o. bioavailable, small-molecule inhibitor of the catalytic activity of c-Met kinase and the NPM-ALK fusion protein. PF-2341066 also potently inhibited NPM-ALK phosphorylation in Karpas299 or SU-DHL-1 ALCL cells (mean IC50 value, 24 nmol/L). In biochemical and cellular screens, PF-2341066 was shown to be selective for c-Met and ALK at pharmacologically relevant concentrations across a panel of >120 diverse kinases. PF-2341066 potently inhibited cell proliferation, which was associated with G1-S–phase cell cycle arrest and induction of apoptosis in ALK-positive ALCL cells (IC50 values, ∼30 nmol/L) but not ALK-negative lymphoma cells. The induction of apoptosis was confirmed using terminal deoxyribonucleotide transferase–mediated nick-end labeling and Annexin V staining (IC50 values, 25–50 nmol/L). P.o. administration of PF-2341066 to severe combined immunodeficient-Beige mice bearing Karpas299 ALCL tumor xenografts resulted in dose-dependent antitumor efficacy with complete regression of all tumors at the 100 mg/kg/d dose within 15 days of initial compound administration. A strong correlation was observed between antitumor response and inhibition of NPM-ALK phosphorylation and induction of apoptosis in tumor tissue. In addition, inhibition of key NPM-ALK signaling mediators, including phospholipase C-γ, signal transducers and activators of transcription 3, extracellular signal-regulated kinases, and Akt by PF-2341066 were observed at concentrations or dose levels, which correlated with inhibition of NPM-ALK phosphorylation and function. Collectively, these data illustrate the potential clinical utility of inhibitors of NPM-ALK in treatment of patients with ALK-positive ALCL. [Mol Cancer Ther 2007;6(12):3314–22]</jats:p>
Journal
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- Molecular Cancer Therapeutics
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Molecular Cancer Therapeutics 6 (12), 3314-3322, 2007-12-01
American Association for Cancer Research (AACR)
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Details 詳細情報について
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- CRID
- 1363670320137508736
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- ISSN
- 15388514
- 15357163
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- Data Source
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- Crossref