SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo

Anne Marie O'Farrell, Tinya J. Abrams, Helene A. Yuen, Theresa J. Ngai, Sharianne G. Louie, Kevin W.H. Yee, Lily M. Wong, Weiru Hong, Leslie B. Lee, Ajia Town, Beverly D. Smolich, William C. Manning, Lesley J. Murray, Michael C. Heinrich, Julie M. Cherrington

    Research output: Contribution to journalArticlepeer-review

    739 Scopus citations

    Abstract

    FLT3 (fms-related tyrosine kinase/Flk2/Stk-2) is a receptor tyrosine kinase (RTK) primarily expressed on hematopoietic cells. In blasts from acute myelogenous leukemia (AML) patients, 2 classes of FLT3 activating mutations have been identified: internal tandem duplication (ITD) mutations in the juxtamembrane domain (25%-30% of patients) and point mutations in the kinase domain activation loop (7%-8% of patients). FLT3-ITD mutations are the most common molecular defect identified in AML and have been shown to be an independent prognostic factor for decreased survival. FLT3-ITD is therefore an attractive molecular target for therapy. SU11248 is a recently described selective inhibitor with selectivity for split kinase domain RTKs, including platelet-derived growth factor receptors, vascular endothelial growth factor receptors, and KIT. We show that SU11248 also has potent activity against wild-type FLT3 (FLT3-WT), FLT3-ITD, and FLT3 activation loop (FLT3-Asp835) mutants in phosphorylation assays. SU11248 inhibits FLT3-driven phosphorylatiori and induces apoptosis in vitro. In addition, SU11248 inhibits FLT3-induced VEGF production. The in vivo efficacy of SU11248 was investigated in 2 FLT3-ITD models: a subcutaneous tumor xenograft model and a bone marrow engraftment model. We show that SU11248 (20 mg/kg/d) dramatically regresses FLT3-ITD tumors in the subcutaneous tumor xenograft model and prolongs survival in the bone marrow engraftment model. Pharmacokinetic and pharmacodynamic analysis in subcutaneous tumors showed that a single administration of an efficacious drug dose potently inhibits FLT3-ITD phosphorylation for up to 16 hours following a single dose. These results suggest that further exploration of SU11248 activity in AML patients is warranted.

    Original languageEnglish (US)
    Pages (from-to)3597-3605
    Number of pages9
    JournalBlood
    Volume101
    Issue number9
    DOIs
    StatePublished - May 1 2003

    ASJC Scopus subject areas

    • Biochemistry
    • Immunology
    • Hematology
    • Cell Biology

    Fingerprint Dive into the research topics of 'SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo'. Together they form a unique fingerprint.

    Cite this