Discovery of a Highly Potent and Selective Indenoindolone Type 1 Pan-FLT3 Inhibitor

John M. Hatcher, Ellen Weisberg, Taebo Sim, Richard M. Stone, Suiyang Liu, James D. Griffin, Nathanael S. Gray

    Research output: Contribution to journalArticlepeer-review

    18 Citations (Scopus)

    Abstract

    For a subpopulation of acute myeloid leukemia (AML) patients, the mutationally activated tyrosine kinase FLT3, has emerged as a promising target for therapy. The development of drug resistance due to mutation is a growing concern for mutant FLT3 inhibitors, such as PKC412, Quizartinib, PLX3397, and Crenolanib. Thus, there is a need to develop novel FLT3 inhibitors that overcome these mutations. Here we report the development of a novel type I ATP competitive inhibitor, JH-IX-179, that is extremely potent and selective for FLT3. JH-IX-179 also has the highest affinity for three constitutively active isoforms of FLT3 (FLT3-ITD, FLT3-N841I, and FLT3-D835V) compared to a panel 456 other kinases. The unique and specific kinase inhibition profile suggests that this chemotype may represent an attractive starting point for the development of further improved FLT3 inhibitors with therapeutic potential in tumors harboring deregulated FLT3 activity.

    Original languageEnglish
    Pages (from-to)476-481
    Number of pages6
    JournalACS Medicinal Chemistry Letters
    Volume7
    Issue number5
    DOIs
    Publication statusPublished - 2016 May 12

    Bibliographical note

    Publisher Copyright:
    © 2016 American Chemical Society.

    Keywords

    • Acute myeloid leukemia
    • FLT3
    • JH-IX-179
    • chemotype
    • kinase inhibition profile

    ASJC Scopus subject areas

    • Biochemistry
    • Drug Discovery
    • Organic Chemistry

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