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[Cancer Research 66, 362-371, January 1, 2006]
© 2006 American Association for Cancer Research


Experimental Therapeutics, Molecular Targets, and Chemical Biology

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

Paul Haluska1, Joan M. Carboni4, David A. Loegering2, Francis Y. Lee4, Mark Wittman5, Mark G. Saulnier5, David B. Frennesson5, Kimberly R. Kalli3, Cheryl A. Conover3, Ricardo M. Attar4, Scott H. Kaufmann2, Marco Gottardis4 and Charles Erlichman1

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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Copyright © 2006 by the American Association for Cancer Research.