Ripretinib (DCC-2618)Is a Switch Control Kinase Inhibitor of a Broad Spectrum of Oncogenic and Drug-Resistant KIT and PDGFRA Variants

Bryan D. Smith, Michael D. Kaufman, Wei Ping Lu, Anu Gupta, Cynthia B. Leary, Scott C. Wise, Thomas J. Rutkoski, Yu Mi Ahn, Gada Al-Ani, Stacie L. Bulfer, Timothy M. Caldwell, Lawrence Chun, Carol L. Ensinger, Molly M. Hood, Arin McKinley, William C. Patt, Rodrigo Ruiz-Soto, Ying Su, Hanumaiah Telikepalli, Ajia TownBenjamin A. Turner, Lakshminarayana Vogeti, Subha Vogeti, Karen Yates, Filip Janku, Albiruni Ryan Abdul Razak, Oliver Rosen, Michael C. Heinrich, Daniel L. Flynn

    Research output: Contribution to journalArticle

    12 Scopus citations

    Abstract

    Ripretinib (DCC-2618)was designed to inhibit the full spectrum of mutant KIT and PDGFRA kinases found in cancers and myeloproliferative neoplasms, particularly in gastrointestinal stromal tumors (GISTs), in which the heterogeneity of drug-resistant KIT mutations is a major challenge. Ripretinib is a “switch-control” kinase inhibitor that forces the activation loop (or activation “switch”)into an inactive conformation. Ripretinib inhibits all tested KIT and PDGFRA mutants, and notably is a type II kinase inhibitor demonstrated to broadly inhibit activation loop mutations in KIT and PDGFRA, previously thought only achievable with type I inhibitors. Ripretinib shows efficacy in preclinical cancer models, and preliminary clinical data provide proof-of-concept that ripretinib inhibits a wide range of KIT mutants in patients with drug-resistant GISTs.

    Original languageEnglish (US)
    Pages (from-to)738-751.e9
    JournalCancer Cell
    Volume35
    Issue number5
    DOIs
    StatePublished - May 13 2019

    Keywords

    • GIST
    • KIT
    • PDGFRA
    • conformational switch control
    • imatinib
    • mastocytosis
    • regorafenib
    • resistance
    • ripretinib
    • sunitinib

    ASJC Scopus subject areas

    • Oncology
    • Cell Biology
    • Cancer Research

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  • Cite this

    Smith, B. D., Kaufman, M. D., Lu, W. P., Gupta, A., Leary, C. B., Wise, S. C., Rutkoski, T. J., Ahn, Y. M., Al-Ani, G., Bulfer, S. L., Caldwell, T. M., Chun, L., Ensinger, C. L., Hood, M. M., McKinley, A., Patt, W. C., Ruiz-Soto, R., Su, Y., Telikepalli, H., ... Flynn, D. L. (2019). Ripretinib (DCC-2618)Is a Switch Control Kinase Inhibitor of a Broad Spectrum of Oncogenic and Drug-Resistant KIT and PDGFRA Variants. Cancer Cell, 35(5), 738-751.e9. https://doi.org/10.1016/j.ccell.2019.04.006