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Blood, 15 October 2004, Vol. 104, No. 8, pp. 2532-2539. Prepublished online as a Blood First Edition Paper on July 15, 2004; DOI 10.1182/blood-2004-05-1851. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-05-1851v1 104/8/2532    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by O'Hare, T. Articles by Druker, B. J. Search for Related Content PubMed PubMed Citation Articles by O'Hare, T. Articles by Druker, B. J. Related Collections Neoplasia Apoptosis Cell Cycle Oncogenes and Tumor Suppressors Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Inhibition of wild-type and mutant Bcr-Abl by AP23464, a potent ATP-based oncogenic protein kinase inhibitor: implications for CML Thomas O'Hare, Roy Pollock, Eric P. Stoffregen, Jeffrey A. Keats, Omar M. Abdullah, Erika M. Moseson, Victor M. Rivera, Hao Tang, Chester A. Metcalf, III, Regine S. Bohacek, Yihan Wang, Raji Sundaramoorthi, William C. Shakespeare, David Dalgarno, Tim Clackson, Tomi K. Sawyer, Michael W. Deininger, and Brian J. Druker From the Howard Hughes Medical Institute, Oregon Health and Science University, Portland; the Division of Hematology and Medical Oncology, Oregon Health and Science University Cancer Institute, Portland; and ARIAD Pharmaceuticals Inc, Cambridge, MA. The deregulated, oncogenic tyrosine kinase Bcr-Abl causes chronic myeloid leukemia (CML). Imatinib mesylate (Gleevec, STI571), a Bcr-Abl kinase inhibitor, selectively inhibits proliferation and promotes apoptosis of CML cells. Despite the success of imatinib mesylate in the treatment of CML, resistance is observed, particularly in advanced disease. The most common imatinib mesylate resistance mechanism involves Bcr-Abl kinase domain mutations that impart varying degrees of drug insensitivity. AP23464, a potent adenosine 5'-triphosphate (ATP)–based inhibitor of Src and Abl kinases, displays antiproliferative activity against a human CML cell line and Bcr-Abl–transduced Ba/F3 cells (IC50 = 14 nM; imatinib mesylate IC50 = 350 nM). AP23464 ablates Bcr-Abl tyrosine phosphorylation, blocks cell cycle progression, and promotes apoptosis of Bcr-Abl–expressing cells. Biochemical assays with purified glutathione S transferase (GST)–Abl kinase domain confirmed that AP23464 directly inhibits Abl activity. Importantly, the low nanomolar cellular and biochemical inhibitory properties of AP23464 extend to frequently observed imatinib mesylate–resistant Bcr-Abl mutants, including nucleotide binding P-loop mutants Q252H, Y253F, E255K, C-terminal loop mutant M351T, and activation loop mutant H396P. AP23464 was ineffective against mutant T315I, an imatinib mesylate contact residue. The potency of AP23464 against imatinib mesylate–refractory Bcr-Abl and its distinct binding mode relative to imatinib mesylate warrant further investigation of AP23464 for the treatment of CML. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. S. Khorashad, H. de Lavallade, J. F. Apperley, D. Milojkovic, A. G. Reid, M. Bua, R. Szydlo, E. Olavarria, J. Kaeda, J. M. Goldman, et al. 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