Discovery of a small-molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFRα, Kit, and Src kinases: Novel type II inhibitor of gatekeeper mutants

Ellen Weisberg, Hwan Geun Choi, Arghya Ray, Rosemary Barrett, Jianming Zhang, Taebo Sim, Wenjun Zhou, Markus Seeliger, Michael Cameron, Mohammed Azam, Jonathan A. Fletcher, Maria Debiec-Rychter, Mark Mayeda, Daisy Moreno, Andrew L. Kung, Pasi Antero Janne, Roya Khosravi-Far, Junia V. Melo, Paul W. Manley, Sophia AdamiaCatherine Wu, Nathanael Gray, James D. Griffin

    Research output: Contribution to journalArticlepeer-review

    64 Citations (Scopus)

    Abstract

    Many clinically validated kinases, such as BCR-ABL, c-Kit, PDGFR, and EGFR, become resistant to adenosine triphosphate-competitive inhibitors through mutation of the so-called gatekeeper amino acid from a threonine to a large hydrophobic amino acid, such as an isoleucine or methionine. We have developed a new class of adenosine triphosphate competitive inhibitors, exemplified by HG-7-85-01, which is capable of inhibiting T315I-BCR-ABL (clinically observed in chronic myeloid leukemia), T670I-c-Kit (clinically observed in gastrointestinal stromal tumors), and T674I/M-PDGFRα (clinically observed in hypereosinophilic syndrome). HG-7-85-01 is unique among all currently reported kinase inhibitors in having the ability to accommodate either a gatekeeper threonine, present in the wild-type forms of these kinases, or a large hydrophobic amino acid without becoming a promiscuous kinase inhibitor. The distinctive ability of HG-7-85-01 to simultaneously inhibit both wild-type and mutant forms of several kinases of clinical relevance is an important step in the development of the next generation of tyrosine kinase inhibitors.

    Original languageEnglish
    Pages (from-to)4206-4216
    Number of pages11
    JournalBlood
    Volume115
    Issue number21
    DOIs
    Publication statusPublished - 2010 May 27

    ASJC Scopus subject areas

    • Biochemistry
    • Immunology
    • Hematology
    • Cell Biology

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