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

Thomas O'Hare, 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 Tyner, Marc Loriaux, Amie S. Corbin, Scott Wardwell, Yaoyu Ning, Jeffrey A. Keats, Yihan Wang, Raji Sundaramoorthi, Mathew ThomasDong Zhou, Joseph Snodgrass, Lois Commodore, Tomi K. Sawyer, David C. Dalgarno, Michael W N Deininger, Brian Druker, Tim Clackson

Research output: Contribution to journalArticle

710 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)401-412
Number of pages12
JournalCancer Cell
Volume16
Issue number5
DOIs
Publication statusPublished - Nov 6 2009

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Keywords

  • CHEMBIO
  • HUMDISEASE

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

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