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Prepublished online as a Blood First Edition Paper on June 14, 2002; DOI 10.1182/blood-2002-02-0531. This Article Full Text (PDF) All Versions of this Article: 2002-02-0531v1 100/8/2941    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 Yee, K. W Articles by Heinrich, M. C Search for Related Content PubMed PubMed Citation Articles by Yee, K. W Articles by Heinrich, M. C Social Bookmarking                   What's this? Submitted February 21, 2002 Accepted May 18, 2002 SU5416 and SU5614 inhibit kinase activity of wild type and mutant FLT3 receptor tyrosine kinase Kevin W Yee, Anne-Marie O'Farrell, Beverly D Smolich, Julie M Cherrington, Gerald McMahon, Cecily L Wait, Laura S McGreevey, Diana J Griffith, and Michael C Heinrich* Hematology and Medical Oncology, Oregon Health & Science University and Portland VA Medical Center, Portland, OR, USA SUGEN, Inc., South San Francisco, CA, USA * Corresponding author; email: heinrich{at}ohsu.edu. Internal tandem duplications (ITDs) in the juxtamembrane portion of FLT3, a Type III receptor tyrosine kinase (RTK), are the most common molecular defect associated with acute myeloid leukemia (AML). The high prevalence of these activating mutations makes them potential targets for molecularly based therapy. Indolinone tyrosine kinase inhibitors have known activity against KIT, another member of the Type III RTK family. Given the conserved homology between members of this family we postulated that the activity of some KIT inhibitors would extend to FLT3. We used various leukemic cell lines (BaF3, MV 4-11, RS 4;11) to test the activity of indolinone compounds against the FLT3 kinase activity of both wild-type and ITD isoforms. Both SU5416 and SU5614 were capable of inhibiting autophosphorylation of ITD and WT FLT3 (SU5416 IC50 100 nM and SU5614 IC50 10 nM). FLT3-dependent activation of the downstream signaling proteins MAPK and STAT5 was also inhibited by treatment in the same concentration ranges. FLT3 inhibition by SU5416 and SU5614 resulted in reduced proliferation (IC50 250 nM and 100 nM respectively) and induction of apoptosis of FLT3 ITD positive leukemic cell lines. Treatment of these cells with an alternative growth factor (GM-CSF) restored MAPK signaling and cellular proliferation, demonstrating specificity of the observed inhibitory effects. 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