Tricyclic quinoxalines as potent kinase inhibitors of PDGFR kinase, Flt3 and Kit

Aviv Gazit, Kevin Yee, Andrea Uecker, Frank D. Böhmer, Tobias Sjöblom, Arne Östman, Johannes Waltenberger, Gershon Golomb, Shmuel Banai, Michael C. Heinrich, Alexander Levitzki

    Research output: Contribution to journalArticle

    58 Scopus citations

    Abstract

    Here we report on novel quinoxalines as highly potent and selective inhibitors of the type III receptor tyrosine kinases PDGFR, FLT3, and KIT. These compounds, tricyclic quinoxalines, were generated in order to improve bioavailability over the highly hydrophobic bicyclic quinoxalines. Four of the highly active compounds were characterized in detail and are shown to inhibit PDGFR kinase activity of the isolated receptor as well as in intact cells in the sub-micromolar concentration range. We show that the most active inhibitor (compound 13, AGL 2043) is ∼15-20 times more potent than its isomer (compound 14, AGL 2044). We therefore compared the three dimensional structures of the two compounds by X-ray crystallography. These compounds are also highly effective in blocking the kinase activity of FLT3, KIT, and the oncogenic protein Tel-PDGFR in intact cells. These compounds are potent inhibitors of the proliferation of pig heart smooth muscle cells. They fully arrest the growth of these cells and the effect is fully reversible. The chemical, biochemical and cellular properties of these compounds as well as the solubility properties make them suitable for development as anti-restenosis and anti-cancer agents.

    Original languageEnglish (US)
    Pages (from-to)2007-2018
    Number of pages12
    JournalBioorganic and Medicinal Chemistry
    Volume11
    Issue number9
    DOIs
    StatePublished - May 1 2003

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Medicine
    • Molecular Biology
    • Pharmaceutical Science
    • Drug Discovery
    • Clinical Biochemistry
    • Organic Chemistry

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  • Cite this

    Gazit, A., Yee, K., Uecker, A., Böhmer, F. D., Sjöblom, T., Östman, A., Waltenberger, J., Golomb, G., Banai, S., Heinrich, M. C., & Levitzki, A. (2003). Tricyclic quinoxalines as potent kinase inhibitors of PDGFR kinase, Flt3 and Kit. Bioorganic and Medicinal Chemistry, 11(9), 2007-2018. https://doi.org/10.1016/S0968-0896(03)00048-8