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    Chem Biol Drug Des. 2010 Feb;75(2):223-7. Epub 2009 Dec 17.

    AP24163 inhibits the gatekeeper mutant of BCR-ABL and suppresses in vitro resistance.

    Azam M, Powers JT, Einhorn W, Huang WS, Shakespeare WC, Zhu X, Dalgarno D, Clackson T, Sawyer TK, Daley GQ.

    Source

    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, The Children's Hospital, Dana Farber Cancer Institute, Brigham and Women's Hospital, Boston, MA, USA.

    Abstract

    Mutation in the ABL kinase domain is the principal mechanism of imatinib resistance in patients with chronic myelogenous leukaemia. The second generation BCR/ABL inhibitors nilotinib and dasatinib effectively inhibit most imatinib resistance variants, but are ineffective against the gatekeeper mutant, T315I. Gatekeeper mutation activates the kinase by stabilizing the hydrophobic spine. Here, we describe that the rationally designed compound AP24163 can inhibit native and gatekeeper mutants of the BCR/ABL kinase. Structural modelling suggests that AP24163 affects the flexibility of the P-loop and destabilizes the active conformation by disrupting the hydrophobic spine. In vitro screening for drug resistance identified clones with compound mutations involving both the P-loop and T315I. Our studies provide structural insights for the design of inhibitors against the gatekeeper mutant and suggest that up-front combination therapy may be required to prevent the emergence of compound-resistant mutations.

    PMID:
    20028401
    [PubMed - indexed for MEDLINE]

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