In Vivo Antitumor Activity of NVP-AEW541-A Novel, Potent, and Selective Inhibitor of the IGF-IR Kinase

Cancer Cell. 2004 Mar;5(3):231-9. doi: 10.1016/s1535-6108(04)00051-0.

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.

MeSH terms

  • 3T3 Cells
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Cell Division
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Enzyme Inhibitors / pharmacology
  • Humans
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • Mice
  • Phosphorylation / drug effects
  • Receptor, IGF Type 1 / drug effects
  • Receptor, IGF Type 1 / metabolism*
  • Receptor, Insulin / drug effects
  • Receptor, Insulin / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • src-Family Kinases / drug effects
  • src-Family Kinases / metabolism

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Receptor, IGF Type 1
  • Receptor, Insulin
  • src-Family Kinases