1. In vivo antitumor activity of NVP-AEW541-A novel, potent, and selective inhibitor of the IGF-IR kinase
- Author
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Robert Cozens, Pascal Furet, Thomas Meyer, Andreas Marti, Stephan Ruetz, Josef Brueggen, Mark A. Pearson, Dean B. Evans, Francesco Hofmann, Jiaping Gao, Johann Zimmermann, Doriano Fabbro, Diana Graus Porta, Janis Liebetanz, Juergen Mestan, Georg Martiny-Baron, Hans-Georg Capraro, and Carlos Garcia-Echeverria
- Subjects
Cancer Research ,MAP Kinase Signaling System ,Antineoplastic Agents ,Apoptosis ,Receptor, IGF Type 1 ,Enzyme activator ,Mice ,In vivo ,Animals ,Humans ,Enzyme Inhibitors ,Phosphorylation ,Receptor ,biology ,Kinase ,Autophosphorylation ,Cell Biology ,3T3 Cells ,Molecular biology ,Small molecule ,Receptor, Insulin ,Enzyme Activation ,Insulin receptor ,src-Family Kinases ,Oncology ,biology.protein ,Cancer research ,Signal transduction ,Cell Division ,Signal Transduction - Abstract
IGF-IR-mediated signaling promotes survival, anchorage-independent growth, and oncogenic transformation, as well as tumor growth and metastasis formation in vivo. NVP-AEW541 is a pyrrolo[2,3-d]pyrimidine derivative small molecular weight kinase inhibitor of the IGF-IR, capable of distinguishing between the IGF-IR (IC50 = 0.086 microM) and the closely related InsR (IC50 = 2.3 microM) in cells. As expected for a specific IGF-IR kinase inhibitor, NVP-AEW541 abrogates IGF-I-mediated survival and colony formation in soft agar at concentrations that are consistent with inhibition of IGF-IR autophosphorylation. In vivo, this orally bioavailable compound inhibits IGF-IR signaling in tumor xenografts and significantly reduces the growth of IGF-IR-driven fibrosarcomas. Thus, NVP-AEW541 represents a class of selective, small molecule IGF-IR kinase inhibitors with proven in vivo antitumor activity and potential therapeutic application.
- Published
- 2003