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
  • 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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