AP24534, a Pan-BCR-ABL Inhibitor for Chronic Myeloid Leukemia, Potently Inhibits the T315I Mutant and Overcomes Mutation-Based Resistance Export

@article{citeulike:6058113, 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-ABLT315I 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-ABLT315I-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.}, author = {O'Hare, Thomas and Shakespeare, William C. and Zhu, Xiaotian and Eide, Christopher A. and Rivera, Victor M. and Wang, Frank and Adrian, Lauren T. and Zhou, Tianjun and Huang, Wei-Sheng and Xu, Qihong and Metcalf, Chester A. and Tyner, Jeffrey W. and Loriaux, Marc M. and Corbin, Amie S. and Wardwell, Scott and Ning, Yaoyu and Keats, Jeffrey A. and Wang, Yihan and Sundaramoorthi, Raji and Thomas, Mathew and Zhou, Dong and Snodgrass, Joseph and Commodore, Lois and Sawyer, Tomi K. and Dalgarno, David C. and Deininger, Michael W. N. and Druker, Brian J. and Clackson, Tim}, citeulike-article-id = {6058113}, citeulike-linkout-0 = {http://www.cell.com/cancer-cell/abstract/S1535-6108(09)00339-0}, day = {6}, keywords = {drug, inhibitor, leukemia, resistance, structure}, month = {November}, number = {5}, pages = {401--412}, posted-at = {2009-11-03 02:26:41}, priority = {2}, title = {AP24534, a Pan-BCR-ABL Inhibitor for Chronic Myeloid Leukemia, Potently Inhibits the T315I Mutant and Overcomes Mutation-Based Resistance}, url = {http://www.cell.com/cancer-cell/abstract/S1535-6108(09)00339-0}, volume = {16}, year = {2009} }

TY - JOUR ID - citeulike:6058113 L3 - citeulike-article-id:6058113 N2 - 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-ABLT315I 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-ABLT315I-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. IS - 5 EP - 412 TI - AP24534, a Pan-BCR-ABL Inhibitor for Chronic Myeloid Leukemia, Potently Inhibits the T315I Mutant and Overcomes Mutation-Based Resistance VL - 16 SP - 401 KW - drug KW - inhibitor KW - leukemia KW - resistance KW - structure AU - O'Hare, Thomas AU - Shakespeare, William AU - Zhu, Xiaotian AU - Eide, Christopher AU - Rivera, Victor AU - Wang, Frank AU - Adrian, Lauren AU - Zhou, Tianjun AU - Huang, Wei-Sheng AU - Xu, Qihong AU - Metcalf, Chester AU - Tyner, Jeffrey AU - Loriaux, Marc AU - Corbin, Amie AU - Wardwell, Scott AU - Ning, Yaoyu AU - Keats, Jeffrey AU - Wang, Yihan AU - Sundaramoorthi, Raji AU - Thomas, Mathew AU - Zhou, Dong AU - Snodgrass, Joseph AU - Commodore, Lois AU - Sawyer, Tomi AU - Dalgarno, David AU - Deininger, Michael AU - Druker, Brian AU - Clackson, Tim PY - 2009/11/06/ UR - http://www.cell.com/cancer-cell/abstract/S1535-6108(09)00339-0 ER -