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Experimental Therapeutics |
Molecular Pharmacology and Chemistry Program [D. W., C. L. L., C. L., A. S., D. R. V., W. G. B., J. R. B., B. C.], Department of Medicine [J. R. B., B. C.], and Core Preparative Synthesis Laboratory [D. R. V., W. G. B.], Memorial Sloan-Kettering Cancer Center [B. C.], New York, New York 10021; Department of Molecular and Cell Biology and Chemistry, Howard Hughes Medical Institute, University of California, Berkeley, California 94720 [B. N., M. A. Y., T. S., J. K.]; and Howard Hughes Medical Institute and Rockefeller University, New York, New York 10021 [B. N., M. A. Y., J. K.]
The early stage of chronic myelogenous leukemia (CML) is caused by the tyrosine kinase Bcr-Abl. Imatinib mesylate (also known as STI-571 and Gleevec), a tyrosine kinase inhibitor, has shown encouraging results in CML clinical trials and has become a paradigm for targeted cancer therapeutics. Recent reports of resistance to imatinib argue for further development of therapies for CML. During studies of signal transduction, we observed that the pyrido[2,3-d]pyrimidine src tyrosine kinase inhibitor PD173955 inhibited Bcr-Abl-dependent cell growth. Subsequently, a related compound, PD180970, was reported as a potent inhibitor of Bcr-Abl. We have compared the potency of these two compounds and four other analogues with imatinib on Bcr-Abl-dependent cell growth, cytokine-dependent cell growth, and tyrosine kinase inhibition. PD173955 inhibited Bcr-Abl-dependent cell growth with an IC50 of 2–35 nM in different cell lines. Fluorescence-activated cell-sorting analyses of cells treated with PD173955 showed cell cycle arrest in G1. PD173955 has an IC50 of 1–2 nM in kinase inhibition assays of Bcr-Abl, and in cellular growth assays it inhibits Bcr-Abl-dependent substrate tyrosine phosphorylation. Of the six pyrido[2,3-d]pyrimidine analogues studied, PD166326 was the most potent inhibitor of Bcr-Abl-dependent cell growth. PD173955 inhibited kit ligand-dependent c-kit autophosphorylation (IC50 = 
25 nM) and kit ligand-dependent proliferation of M07e cells (IC50 = 40 nM) but had a lesser effect on interleukin 3-dependent (IC50 = 250 nM) or granulocyte macrophage colony-stimulating factor (IC50 = 1 µM)-dependent cell growth. These compounds are potent inhibitors of both the Bcr-Abl and c-kit receptor tyrosine kinases and deserve further study as potential treatments for both CML and for diseases in which c-kit has a role.
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