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Research Articles: Therapeutics, Targets, and Development

Novel compounds with antiproliferative activity against imatinib-resistant cell lines

¹ Sidney Kimmel Cancer Center, San Diego, California; ² Yale University, New Haven, Connecticut; ³ Imperial College and Hammersmith Hospital, London, United Kingdom; and ⁴ Dana-Farber Cancer Center, Boston, Massachusetts

Requests for reprints: Albert Deisseroth, Sidney Kimmel Cancer Center, 10835 Altman Row, San Diego, CA 92121. Phone: 858-410-4205; Fax: 858-450-3251. E-mail: adeisseroth{at}skcc.org

Abstract

Chronic myelogenous leukemia is caused by the Bcr-Abl hybrid gene that encodes the p210Bcr-Abl chimeric oncoprotein. Although it reduces the total body burden of leukemia cells, the use of imatinib mesylate as a single agent may be accompanied by the evolution of resistance due mainly to the acquisition of point mutations. Imatinib has been combined with drugs that inhibit both the active and the inactive states of the p210Bcr-Abl kinase. These combinations have reduced but not completely eliminated the rate at which point mutations are acquired in the p210Bcr-Abl kinase. Thus, it is important to identify additional new inhibitors of the p210Bcr-Abl kinase. One possible method to prevent evolution of resistance is to simultaneously use multiple kinase inhibitors each with a different mechanism of action. To identify such a new class of inhibitors that could suppress the growth of chronic myelogenous leukemia cells and prevent the evolution of cells that are resistant to imatinib, we screened two low-complexity libraries of compounds based on planar and linear scaffolds. These libraries were screened using a cell-based assay for molecules that suppress p210Bcr-Abl–dependent cell growth. The application of this method resulted in the isolation of two new classes of drugs, both of which inhibited imatinib-resistant cells in the low micromolar range. Some of these drugs were potent inhibitors not only of Abl tyrosine kinase but also of the Src, Lyn, and Fyn tyrosine kinases. [Mol Cancer Ther 2007;6(2):655–66]

Grant support: NIH/National Cancer Institute grant P01 CA49639-09 (A. Deisseroth and D.J. Austin), Department of Defense Chronic Myelogenous Leukemia Program grant W81XWH-06 (A. Deisseroth), George and Barbara Bush Leukemia Research Fund (A. Deisseroth), ARITMO/ABMT, Lauri Strauss Leukemia Foundation, National Leukemia Research Association (E.I. Lerma), Leukemia/Lymphoma Society of the USA, The Brian Schultz Foundation, The Anthony Dewitt Melanoma Research Fund, Sidney Kimmel Foundation (Sidney Kimmel Cancer Center), Leukemia Research Fund of Great Britain (J.V. Melo and A. Tipping), and Department of Chemistry at Yale University Anderson Endowed Postdoctoral Fellowship (V-A. Nguyen).

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 11/17/04; revised 9/21/06; accepted 12/18/06.