| Literature DB >> 19878872 |
Thomas O'Hare1, William C Shakespeare, Xiaotian Zhu, Christopher A Eide, Victor M Rivera, Frank Wang, Lauren T Adrian, Tianjun Zhou, Wei-Sheng Huang, Qihong Xu, Chester A Metcalf, Jeffrey W Tyner, Marc M Loriaux, Amie S Corbin, Scott Wardwell, Yaoyu Ning, Jeffrey A Keats, Yihan Wang, Raji Sundaramoorthi, Mathew Thomas, Dong Zhou, Joseph Snodgrass, Lois Commodore, Tomi K Sawyer, David C Dalgarno, Michael W N Deininger, Brian J Druker, Tim Clackson.
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.Entities:
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Year: 2009 PMID： 19878872 PMCID： PMC2804470 DOI： 10.1016/j.ccr.2009.09.028
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743