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Bis(1H-2-indolyl)-1-methanones as inhibitors of the hematopoietic tyrosine kinase Flt3

Leukemia volume 16, pages 1528–1534 (2002)Cite this article

Abstract

Aberrant expression and activating mutations of the class III receptor tyrosine kinase Flt3 (Flk-2, STK-1) have been linked to poor prognosis in acute myeloid leukemia (AML). Inhibitors of Flt3 tyrosine kinase activity are, therefore, of interest as potential therapeutic compounds. We previously described bis(1H-2-indolyl)-1-methanones as a novel class of selective inhibitors for platelet-derived growth factor receptors (PDGFR). Several bis(1H-2-indolyl)-1-methanone derivatives, represented by the compounds D-64406 and D-65476, are also potent inhibitors of Flt3. They inhibit proliferation of TEL-Flt3-transfected BA/F3 cells with IC50 values of 0.2–0.3 μM in the absence of IL-3 but >10 μM in the presence of IL-3. Ligand-stimulated autophosphorylation of Flt3 in EOL-1 cells and corresponding downstream activation of Akt/PKB are effectively inhibited by bis(1H-2-indolyl)-1-methanones whereas autophosphorylation of c-Kit/SCF receptor or c-Fms/CSF-1 receptor is less sensitive or insensitive, respectively. Flt3 kinase purified by different methods is potently inhibited in vitro, demonstrating a direct mechanism of inhibition. 32D cells, expressing a constitutively active Flt3 variant with internal tandem duplication are greatly sensitized to radiation-induced apoptosis in the presence of D-64406 or D-65476 in the absence but not in the presence of IL-3. Thus, bis(1H-2-indolyl)-1-methanones are potential candidates for the treatment of Flt3-driven leukemias.

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Acknowledgements

This work was in part supported by a grant from the German Federal Ministry for education and Science (BEO 0311334 to FDB, TB and SM); a grant from Deutsche Krebshilfe, eV (10-1717-Do I to FDB and SM); from the Deutsche Forschungsgemeinschaft (Se 600/2-4) and from the IZKF and IMF Münster (to HS); and a grant from the NCI (CA70970) to DS.

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  1. T Beckers

    Present address: Byk Gulden GmbH, Disease Area Oncology, Konstanz, Germany

Authors and Affiliations

  1. Research Unit Molecular Cell Biology, Medical Faculty, Friedrich Schiller University, Jena, Germany

    S Teller, D Krämer, S-A Böhmer & F-D Böhmer

  2. Johns Hopkins University, School of Medicine, Pediatric Oncology, Baltimore, MD, USA

    KF Tse & D Small

  3. Faculty of Chemistry and Pharmacy, Institute of Pharmacy, University of Regensburg, Regensburg, Germany

    S Mahboobi

  4. ASTA Medica AG, Frankfurt/Main, Germany

    C Wallrapp & T Beckers

  5. Department of Medicine/Hematology and Oncology, University of Münster, Germany

    K Kratz-Albers, J Schwäble & H Serve

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Teller, S., Krämer, D., Böhmer, SA. et al. Bis(1H-2-indolyl)-1-methanones as inhibitors of the hematopoietic tyrosine kinase Flt3. Leukemia 16, 1528–1534 (2002). https://doi.org/10.1038/sj.leu.2402630

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