SEARCH:   Advanced

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 (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 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 Search for Related Content PubMed PubMed Citation Articles by Corbin, A. S Articles by Deininger, M. W Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted December 16, 2004 Accepted February 21, 2005 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 Sawyer, Michael C Heinrich, Brian J Druker, and Michael W Deininger* Oregon Health and Science University, Cancer Institute, Portland, OR, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA Oregon Health and Science University, Cancer Institute, Portland, OR, USA ARIAD Pharmaceuticals, Cambridge, MA, USA Oregon Health and Science University, Cancer Institute, Portland, OR, USA; Portland VA Medical Center, Oregon Health and Science University, Portland, OR, USA * Corresponding author; email: deininge{at}ohsu.edu. Oncogenic mutations of the Kit receptor tyrosine kinase occur in several types of malignancy. Juxtamembrane domain mutations are common in gastrointestinal stromal tumors, while 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 and have been largely resistant to targeted inhibition. We determined the sensitivities of both Kit mutant classes to the 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 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]

	Copyright © 2005 by American Society of Hematology         Online ISSN: 1528-0020