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-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.

• Authors: 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 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
• Journal: Cancer cell (Cancer Cell) Vol. 16 Issue 5 Pg. 401-12 (Nov 06 2009) ISSN: 1878-3686 [Electronic] United States
• PMID: 19878872 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Imidazoles
• Protein Kinase Inhibitors
• Pyridazines
• ponatinib
• Fusion Proteins, bcr-abl
• Proto-Oncogene Proteins c-abl

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Cell Growth Processes (drug effects)
• Cell Line, Tumor
• Crystallography, X-Ray
• Fusion Proteins, bcr-abl (antagonists & inhibitors, chemistry, genetics, metabolism)
• Humans
• Imidazoles (chemistry, pharmacology)
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, enzymology, genetics, pathology)
• Mice
• Mice, SCID
• Models, Molecular
• Protein Kinase Inhibitors (chemistry, pharmacology)
• Proto-Oncogene Proteins c-abl (antagonists & inhibitors, chemistry, genetics, metabolism)
• Pyridazines (chemistry, pharmacology)
• Signal Transduction (drug effects)