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Research Articles: Development

Diarylureas are small-molecule inhibitors of insulin-like growth factor I receptor signaling and breast cancer cell growth

¹ Diabetes and Endocrine Research and ² Department of Surgery, University of California, San Francisco/Mt. Zion Medical Center; ³ Departments of Medicine, and Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, San Francisco, California; and ⁴ Telik, Inc., Palo Alto, California

Requests for reprints: Jack Youngren, Division of Diabetes and Endocrine Research University of California, San Francisco/Mt. Zion Medical Center, Box 1616, San Francisco, CA 94143-1616. Phone: 415-885-7725; Fax: 415-885-7727. E-mail: drjack{at}itsa.ucsf.edu

Abstract

In breast and certain other cancers, receptor tyrosine kinases, including the insulin-like growth factor I receptor (IGF-IR), play an important role in promoting the oncogenic process. The IGF-IR is therefore an important target for developing new anti–breast cancer therapies. An initial screening of a chemical library against the IGF-IR in breast cancer cells identified a diaryl urea compound as a potent inhibitor of IGF-IR signaling. This class of compounds has not been studied as inhibitors of the IGF-IR. We studied the effectiveness of one diaryl urea compound, PQ401, at antagonizing IGF-IR signaling and inhibiting breast cancer cell growth in culture and in vivo. PQ401 inhibited autophosphorylation of the IGF-IR in cultured human MCF-7 cells with an IC₅₀ of 12 µmol/L and autophosphorylation of the isolated kinase domain of the IGF-IR with an IC₅₀ <1 µmol/L. In addition, PQ401 inhibited the growth of cultured breast cancer cells in serum at 10 µmol/L. PQ401 was even more effective at inhibiting IGF-I-stimulated growth of MCF-7 cells (IC₅₀, 6 µmol/L). Treatment of MCF-7 cells with PQ401 was associated with a decrease in IGF-I-mediated signaling through the Akt antiapoptotic pathway. Twenty-four hours of treatment with 15 µmol/L PQ401 induced caspase-mediated apoptosis. In vivo, treatment with PQ401 (i.p. injection thrice a week) reduced the growth rate of MCNeuA cells implanted into mice. These studies indicate that diaryl urea compounds are potential new agents to test in the treatment of breast and other IGF-I-sensitive cancers. [Mol Cancer Ther 2006;5(4):1079–86]

Grant support: California Breast Cancer Research Program grant 8WB-0099 (J.F. Youngren), the University of California, San Francisco Academic Senate Committee on Research (J.F. Youngren), National Cancer Institute grant 5 U-56 CA92616-04 (J.F. Youngren), the John Kerner Fund, and the Jay Gershow Fund.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 9/30/05; revised 1/20/06; accepted 2/15/06.

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