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Blood, 1 December 2004, Vol. 104, No. 12, pp. 3754-3757. Prepublished online as a Blood First Edition Paper on August 10, 2004; DOI 10.1182/blood-2004-06-2189. This Article Full Text (PDF) All Versions of this Article: 2004-06-2189v1 104/12/3754    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 June 9, 2004 Accepted July 23, 2004 Sensitivity of oncogenic KIT mutants to the kinase inhibitors MLN518 and PD180970 Amie S Corbin, Ian J Griswold, Paul La Rosee, Kevin W Yee, Michael C Heinrich, Corinne L Reimer, Brian J Druker, and Michael W Deininger* Oregon Health and Science University Cancer Institute, Portland, OR, USA; Howard Hughes Medical Institute, USA Fakultat fur klinische Medizin, III. Medizinische Universitatsklinik, Mannheim der Universitat, Heidelberg, Germany Portland VA Medical Center, Oregon Health and Science University Cancer Institute, Portland, OR, USA Millennium Pharmaceuticals Inc., Cambridge, MA, USA Oregon Health and Science University Cancer Institute, Portland, OR, USA * Corresponding author; email: deininge{at}ohsu.edu. Oncogenic mutations of the receptor tyrosine kinase KIT occur in gastrointestinal stromal tumors (GIST), some cases of acute myelogenous leukemia (AML) and systemic mastocytosis (SM). GISTs commonly contain mutations of the KIT juxtamembrane region while SM and AML harbor active site KIT mutations. Imatinib, which potently inhibits juxtamembrane mutants, is effective for the treatment of GISTs but has no activity against active site mutants. We analyzed the inhibitory potential of two small molecule inhibitors, MLN518 and PD180970 against different classes of KIT mutants. Both compounds inhibit the growth of cell lines expressing juxtamembrane mutant KIT. MLN518 additionally targets active site mutant cell lines, inhibiting cell proliferation, KIT and Stat3 phosphorylation and inducing apoptosis at concentrations that may be clinically achievable. As phase I clinical trials of MLN518 in AML have shown little toxicity, our data suggest MLN518 is a promising candidate for the treatment of SM or AML with KIT mutations. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Fernandez, A. Sanguino, Z. Peng, A. Crespo, E. Ozturk, X. Zhang, S. Wang, W. Bornmann, and G. Lopez-Berestein Rational Drug Redesign to Overcome Drug Resistance in Cancer Therapy: Imatinib Moving Target Am. Assoc. Cancer Res. Educ. Book, April 12, 2008; 2008(1): 589 - 599. [Abstract] [Full Text] [PDF] A. Tefferi, S. Verstovsek, and A. Pardanani How we diagnose and treat WHO-defined systemic mastocytosis in adults Haematologica, January 1, 2008; 93(1): 6 - 9. [Full Text] [PDF] A. K. Todd, S. M. Haider, G. N. Parkinson, and S. Neidle Sequence occurrence and structural uniqueness of a G-quadruplex in the human c-kit promoter Nucleic Acids Res., September 27, 2007; 35(17): 5799 - 5808. 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