In vitro and in vivo antitumor effects of the dual insulin-like growth factor-I/insulin receptor inhibitor, BMS-554417

Cancer Res. 2006 Jan 1;66(1):362-71. doi: 10.1158/0008-5472.CAN-05-1107.

Abstract

The insulin-like growth factor receptor (IGF-IR) and insulin receptor are either overactivated and/or overexpressed in a wide range of tumor types and contribute to tumorigenicity, proliferation, metastasis, and drug resistance. Here, we show that BMS-554417, a novel small molecule developed as an inhibitor of IGF-IR, inhibits IGF-IR and insulin receptor kinase activity and proliferation in vitro, and reduces tumor xenograft size in vivo. In a series of carcinoma cell lines, the IC50 for proliferation ranged from 120 nmol/L (Colo205) to >8.5 micromol/L (OV202). The addition of stimulatory ligands was unnecessary for the antiproliferative effect in MCF-7 and OV202 cells. BMS-554417 treatment inhibited IGF-IR and insulin receptor signaling through extracellular signal-related kinase as well as the phosphoinositide 3-kinase/Akt pathway, as evidenced by decreased Akt phosphorylation at Ser473. At doses that inhibited proliferation, the compound also caused a G0-G1 arrest and prevented nuclear accumulation of cyclin D1 in response to LR3 IGF-I. In Jurkat T-cell leukemia cells, this agent triggered apoptotic cell death via the mitochondrial pathway. BMS-554417 was orally bioavailable and significantly inhibited the growth of IGF1R-Sal tumor xenografts in vivo. BMS-554417 is a member of a novel class of IGF-IR/insulin receptor inhibitors that have potential clinical applications because of their antiproliferative and proapoptotic activity in vitro and in vivo.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism
  • Caspases / metabolism
  • Cell Growth Processes / drug effects
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cyclin D1 / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Activation
  • Female
  • G1 Phase / drug effects
  • Humans
  • Insulin-Like Growth Factor I / antagonists & inhibitors
  • Mice
  • Mice, Nude
  • Mitochondria / drug effects
  • Mitochondria / physiology
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / metabolism
  • Phosphorylation / drug effects
  • Piperazines / pharmacology*
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Pyridones / pharmacology*
  • Receptor, IGF Type 1 / antagonists & inhibitors*
  • Receptor, IGF Type 1 / metabolism
  • Receptor, Insulin / antagonists & inhibitors*
  • Receptor, Insulin / metabolism
  • S Phase / drug effects

Substances

  • Antineoplastic Agents
  • BMS-554417
  • Piperazines
  • Pyridones
  • Cyclin D1
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1
  • Receptor, Insulin
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase Kinases
  • Caspases