In vivo antitumor activity of NVP-AEW541 -: A novel, potent, and selective inhibitor of the IGF-IR kinase

被引:469
作者
García-Echeverría, C
Pearson, MA
Marti, A
Meyer, T
Mestan, J
Zimmermann, J
Gao, JP
Brueggen, J
Capraro, HG
Cozens, R
Evans, DB
Fabbro, D
Furet, P
Porta, DG
Liebetanz, J
Martiny-Baron, G
Ruetz, S
Hofmann, F [1 ]
机构
[1] Novartis Pharma AG, Novartis Inst BioMed Res, CH-4002 Basel, Switzerland
[2] Novartis Inst BioMed Res Inc, Cambridge, MA 02138 USA
关键词
D O I
10.1016/S1535-6108(04)00051-0
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 muM) and the closely related InsR (IC50 = 2.3 muM) 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.
引用
收藏
页码:231 / 239
页数:9
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