SU5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase

Kevin Yee, Anne Marie O'Farrell, Beverly D. Smolich, Julie M. Cherrington, Gerald McMahon, Cecily L. Wait, Laura S. McGreevey, Diana J. Griffith, Michael Heinrich

    Research output: Contribution to journalArticle

    166 Citations (Scopus)

    Abstract

    Internal tandem duplication (ITD) in the juxtamembrane portion of Fms-like tyrosine kinase 3 (FLT3), a type III receptor tyrosine kinase (RTK), is the most common molecular defect associated with acute myeloid leukemia (AML). The high prevalence of this activating mutation makes it a potential target 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 (WT) and ITD isoforms. Both SU5416 and SU5614 were capable of inhibiting autophosphorylation of ITD and WT FLT3 (SU5416 concentration that inhibits 50% [IC50], 100 nM; and SU5614 IC50 10 nM). FLT3-dependent activation of the downstream signaling proteins mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 5 (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 (granulocyte-macrophage colony-stimulating factor [GM-CSF]) restored MAPK signaling and cellular proliferation, demonstrating specificity of the observed inhibitory effects. We conclude that SU5416 and SU5614 are potent inhibitors of FLT3. Our finding that inhibition of FLT3 induces apoptosis of leukemic cells supports the feasibility of targeting FLT3 as a novel treatment strategy for AML.

    Original languageEnglish (US)
    Pages (from-to)2941-2949
    Number of pages9
    JournalBlood
    Volume100
    Issue number8
    DOIs
    StatePublished - Oct 15 2002

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    fms-Like Tyrosine Kinase 3
    Receptor Protein-Tyrosine Kinases
    Protein-Tyrosine Kinases
    Phosphotransferases
    Inhibitory Concentration 50
    Cells
    Mitogen-Activated Protein Kinases
    Acute Myeloid Leukemia
    3-tyrosine
    Semaxinib
    STAT5 Transcription Factor
    Apoptosis
    Cell Line
    Therapeutics
    Granulocyte-Macrophage Colony-Stimulating Factor
    Intercellular Signaling Peptides and Proteins
    Protein Isoforms

    ASJC Scopus subject areas

    • Hematology

    Cite this

    Yee, K., O'Farrell, A. M., Smolich, B. D., Cherrington, J. M., McMahon, G., Wait, C. L., ... Heinrich, M. (2002). SU5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase. Blood, 100(8), 2941-2949. https://doi.org/10.1182/blood-2002-02-0531

    SU5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase. / Yee, Kevin; O'Farrell, Anne Marie; Smolich, Beverly D.; Cherrington, Julie M.; McMahon, Gerald; Wait, Cecily L.; McGreevey, Laura S.; Griffith, Diana J.; Heinrich, Michael.

    In: Blood, Vol. 100, No. 8, 15.10.2002, p. 2941-2949.

    Research output: Contribution to journalArticle

    Yee, K, O'Farrell, AM, Smolich, BD, Cherrington, JM, McMahon, G, Wait, CL, McGreevey, LS, Griffith, DJ & Heinrich, M 2002, 'SU5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase', Blood, vol. 100, no. 8, pp. 2941-2949. https://doi.org/10.1182/blood-2002-02-0531
    Yee K, O'Farrell AM, Smolich BD, Cherrington JM, McMahon G, Wait CL et al. SU5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase. Blood. 2002 Oct 15;100(8):2941-2949. https://doi.org/10.1182/blood-2002-02-0531
    Yee, Kevin ; O'Farrell, Anne Marie ; Smolich, Beverly D. ; Cherrington, Julie M. ; McMahon, Gerald ; Wait, Cecily L. ; McGreevey, Laura S. ; Griffith, Diana J. ; Heinrich, Michael. / SU5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase. In: Blood. 2002 ; Vol. 100, No. 8. pp. 2941-2949.
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    abstract = "Internal tandem duplication (ITD) in the juxtamembrane portion of Fms-like tyrosine kinase 3 (FLT3), a type III receptor tyrosine kinase (RTK), is the most common molecular defect associated with acute myeloid leukemia (AML). The high prevalence of this activating mutation makes it a potential target 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 (WT) and ITD isoforms. Both SU5416 and SU5614 were capable of inhibiting autophosphorylation of ITD and WT FLT3 (SU5416 concentration that inhibits 50{\%} [IC50], 100 nM; and SU5614 IC50 10 nM). FLT3-dependent activation of the downstream signaling proteins mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 5 (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 (granulocyte-macrophage colony-stimulating factor [GM-CSF]) restored MAPK signaling and cellular proliferation, demonstrating specificity of the observed inhibitory effects. We conclude that SU5416 and SU5614 are potent inhibitors of FLT3. Our finding that inhibition of FLT3 induces apoptosis of leukemic cells supports the feasibility of targeting FLT3 as a novel treatment strategy for AML.",
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    AU - Yee, Kevin

    AU - O'Farrell, Anne Marie

    AU - Smolich, Beverly D.

    AU - Cherrington, Julie M.

    AU - McMahon, Gerald

    AU - Wait, Cecily L.

    AU - McGreevey, Laura S.

    AU - Griffith, Diana J.

    AU - Heinrich, Michael

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