@article{556178f85dfb469299601fde3889350f,
title = "AP24534, a Pan-BCR-ABL Inhibitor for Chronic Myeloid Leukemia, Potently Inhibits the T315I Mutant and Overcomes Mutation-Based Resistance",
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.",
keywords = "CHEMBIO, HUMDISEASE",
author = "Thomas O'Hare and Shakespeare, {William C.} and Xiaotian Zhu and Eide, {Christopher A.} and Rivera, {Victor M.} and Frank Wang and Adrian, {Lauren T.} and Tianjun Zhou and Huang, {Wei Sheng} and Qihong Xu and Metcalf, {Chester A.} and Tyner, {Jeffrey W.} and Loriaux, {Marc M.} and Corbin, {Amie S.} and Scott Wardwell and Yaoyu Ning and Keats, {Jeffrey A.} and Yihan Wang and Raji Sundaramoorthi and Mathew Thomas and Dong Zhou and Joseph Snodgrass and Lois Commodore and Sawyer, {Tomi K.} and Dalgarno, {David C.} and Deininger, {Michael W.N.} and Druker, {Brian J.} and Tim Clackson",
note = "Funding Information: The authors thank D. Wen, I. Chen, G. Banda, L. Cai, J. Romero, S. Das, S. Lentini, and S. Liu for chemical synthesis; S. Lamore for biological experiments; K. Russian, M. Broudy, and N. Narasimhan for pharmacokinetic analyses and discussions; J. Iuliucci for discussions pertaining to pharmacology; and M. Wong for enzymatic assays. W.C.S., X.Z., V.M.R, F.W., T.Z., W.H., S.W., Y.N., J.A.K., Y.W., M.T., L.C., D.C.D., and T.C. are employees of ARIAD Pharmaceuticals, Inc. M.W.N.D. serves as a consultant for Novartis and Bristol-Myers Squibb and receives research support from Calistoga Pharmaceuticals and Genzyme. OHSU and B.J.D. have a financial interest in MolecularMD. Technology used in this research has been licensed to MolecularMD. This potential conflict of interest has been reviewed and managed by the OHSU Conflict of Interest in Research Committee and the Integrity Program Oversight Council. OHSU has clinical trial contracts with ARIAD, Novartis, and Bristol-Myers Squibb to pay for patient costs, nurse and data manager salaries, and institutional overhead. B.J.D. and M.W.N.D. do not derive salary, nor do their laboratories receive funds, from these contracts. The research was supported in part by funding from Howard Hughes Medical Institute and The Leukemia & Lymphoma Society 7393-06. ",
year = "2009",
month = nov,
day = "6",
doi = "10.1016/j.ccr.2009.09.028",
language = "English (US)",
volume = "16",
pages = "401--412",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "5",
}