Title of article :
In vivo antitumor activity of NVP-AEW541—A novel, potent, and selective inhibitor of the IGF-IR kinase
Author/Authors :
Carlos Garcia-Echeverria، نويسنده , , Carlos and Pearson، نويسنده , , Mark A and Marti، نويسنده , , Andreas and Meyer، نويسنده , , Thomas and Mestan، نويسنده , , Juergen and Zimmermann، نويسنده , , Johann and Gao، نويسنده , , Jiaping and Brueggen، نويسنده , , Josef and Capraro، نويسنده , , Hans-Georg and Cozens، نويسنده , , Robert and Evans، نويسنده , , Dean B and Fabbro، نويسنده , , Doriano and Furet، نويسنده , , Pascal and Porta، نويسنده , , Diana Graus and Liebetanz، نويسنده , , Janis and Martiny-Baron، نويسنده , , Georg and Ruetz، نويسنده , , Stephan and Hofmann، نويسنده , , Francesco، نويسنده ,
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 μM) and the closely related InsR (IC50 = 2.3 μM) 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.
