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

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

  • Cancer Cell. 2009 Nov 6;16(5):401-12. doi: 10.1016/j.ccr.2009.09.028.
Thomas O'Hare 1,  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 3rd,  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
Affiliations

Affiliation

  • 1 Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, OR 97239, USA.
PMID: 19878872 DOI: 10.1016/j.ccr.2009.09.028
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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