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      AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance.

      Cancer Cell

      Animals, Antineoplastic Agents, chemistry, pharmacology, Cell Growth Processes, drug effects, Cell Line, Tumor, Crystallography, X-Ray, Fusion Proteins, bcr-abl, antagonists & inhibitors, genetics, metabolism, Humans, Imidazoles, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, drug therapy, enzymology, pathology, Mice, Mice, SCID, Models, Molecular, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-abl, Pyridazines, Signal Transduction

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          Abstract

          Inhibition of BCR-ABL by imatinib induces durable responses in many patients with chronic myeloid leukemia (CML), but resistance attributable to kinase domain mutations can lead to relapse and a switch to second-line therapy with nilotinib or dasatinib. Despite three approved therapeutic options, the cross-resistant BCR-ABL(T315I) mutation and compound mutants selected on sequential inhibitor therapy remain major clinical challenges. We report design and preclinical evaluation of AP24534, a potent, orally available multitargeted kinase inhibitor active against T315I and other BCR-ABL mutants. AP24534 inhibited all tested BCR-ABL mutants in cellular and biochemical assays, suppressed BCR-ABL(T315I)-driven tumor growth in mice, and completely abrogated resistance in cell-based mutagenesis screens. Our work supports clinical evaluation of AP24534 as a pan-BCR-ABL inhibitor for treatment of CML.

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          Author and article information

          Journal
          19878872
          2804470
          10.1016/j.ccr.2009.09.028

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