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In vitro and In vivo Antitumor Effects of the Dual Insulin-Like Growth Factor-I/Insulin Receptor Inhibitor, BMS-554417

Divisions of ¹ Medical Oncology, ² Developmental Oncology Research, and ³ Endocrinology and Metabolism, Mayo Clinic College of Medicine, Rochester, Minnesota; ⁴ Oncology Drug Discovery, Pharmaceutical Research Institute, Bristol-Myers Squibb Co., Princeton, New Jersey; and ⁵ Discovery Chemistry, Bristol-Myers Squibb Co., Wallingford, Connecticut

Requests for reprints: Charles Erlichman, Division of Medical Oncology, Guggenheim 1311, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905. Phone: 507-284-3514; Fax: 507-266-5146; E-mail: erlichman.charles{at}mayo.edu.

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 µmol/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. (Cancer Res 2006; 66(1): 362-71)

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