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Blood, 1 July 2005, Vol. 106, No. 1, pp. 227-234. Prepublished online as a Blood First Edition Paper on March 3, 2005; DOI 10.1182/blood-2004-12-4771. This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: 2004-12-4771v1 106/1/227    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 Corbin, A. S. Articles by Deininger, M. W. N. Search for Related Content PubMed PubMed Citation Articles by Corbin, A. S. Articles by Deininger, M. W. N. Related Collections Neoplasia Oncogenes and Tumor Suppressors Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA In vitro and in vivo activity of ATP-based kinase inhibitors AP23464 and AP23848 against activation-loop mutants of Kit Amie S. Corbin, Shadmehr Demehri, Ian J. Griswold, Yihan Wang, Chester A. Metcalf, III, Raji Sundaramoorthi, William C. Shakespeare, Joseph Snodgrass, Scott Wardwell, David Dalgarno, John Iuliucci, Tomi K. Sawyer, Michael C. Heinrich, Brian J. Druker, and Michael W. N. Deininger From the Oregon Health and Science University, Cancer Institute, Portland, OR; Howard Hughes Medical Institute, Chevy Chase, MD; ARIAD Pharmaceuticals, Cambridge, MA; and Portland VA Medical Center, Oregon Health and Science University, Portland, OR. Oncogenic mutations of the Kit receptor tyrosine kinase occur in several types of malignancy. Juxtamembrane domain mutations are common in gastrointestinal stromal tumors, whereas mutations in the kinase activation loop, most commonly D816V, are seen in systemic mastocytosis and acute myelogenous leukemia. Kit activation-loop mutants are insensitive to imatinib mesylate and have been largely resistant to targeted inhibition. We determined the sensitivities of both Kit mutant classes to the adenosine triphosphate (ATP)–based inhibitors AP23464 and AP23848. In cell lines expressing activation-loop mutants, low-nM concentrations of AP23464 inhibited phosphorylation of Kit and its downstream targets Akt and signal transducer and activator of transcription 3 (STAT3). This was associated with cell-cycle arrest and apoptosis. Wild-type Kit–and juxtamembrane-mutant–expressing cell lines required considerably higher concentrations for equivalent inhibition, suggesting a therapeutic window in which cells harboring D816V Kit could be eliminated without interfering with normal cellular function. Additionally, AP23464 did not disrupt normal hematopoietic progenitor-cell growth at concentrations that inhibited activation-loop mutants of Kit. In a murine model, AP23848 inhibited activation-loop mutant Kit phosphorylation and tumor growth. Thus, AP23464 and AP23848 potently and selectively target activation-loop mutants of Kit in vitro and in vivo and could have therapeutic potential against D816V-expressing malignancies. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Pan, A. Quintas-Cardama, H. M. Kantarjian, C. Akin, T. Manshouri, P. Lamb, J. E. Cortes, A. Tefferi, F. J. Giles, and S. Verstovsek EXEL-0862, a novel tyrosine kinase inhibitor, induces apoptosis in vitro and ex vivo in human mast cells expressing the KIT D816V mutation Blood, January 1, 2007; 109(1): 315 - 322. [Abstract] [Full Text] [PDF] N. P. Shah, F. Y. Lee, R. Luo, Y. Jiang, M. Donker, and C. Akin Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis Blood, July 1, 2006; 108(1): 286 - 291. [Abstract] [Full Text] [PDF] M. M. Schittenhelm, S. Shiraga, A. Schroeder, A. S. Corbin, D. Griffith, F. Y. Lee, C. Bokemeyer, M. W.N. Deininger, B. J. Druker, and M. C. Heinrich Dasatinib (BMS-354825), a Dual SRC/ABL Kinase Inhibitor, Inhibits the Kinase Activity of Wild-Type, Juxtamembrane, and Activation Loop Mutant KIT Isoforms Associated with Human Malignancies Cancer Res., January 1, 2006; 66(1): 473 - 481. [Abstract] [Full Text] [PDF] J. M. Summy, J. G. Trevino, D. P. Lesslie, C. H. Baker, W. C. Shakespeare, Y. Wang, R. Sundaramoorthi, C. A. Metcalf III, J. A. Keats, T. K. Sawyer, et al. AP23846, a novel and highly potent Src family kinase inhibitor, reduces vascular endothelial growth factor and interleukin-8 expression in human solid tumor cell lines and abrogates downstream angiogenic processes Mol. Cancer Ther., December 1, 2005; 4(12): 1900 - 1911. [Abstract] [Full Text] [PDF]

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