In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants.

By T. O'hare, D. Walters, Eric P. Stoffregen, Taiping Jia, P. Manley, J. Mestan, S. Cowan-Jacob, F. Lee, M. Heinrich, M. Deininger and 1 more. Cancer Research, 2005

1,099 citations recorded by the source corpus.

Imatinib, a Bcr-Abl tyrosine kinase inhibitor, is a highly effective therapy for patients with chronic myelogenous leukemia (CML). Despite durable responses in most chronic phase patients, relapses have been observed and are much more prevalent in patients with advanced disease. The most common mechanism of acquired imatinib resistance has been traced to Bcr-Abl kinase domain mutations with decreased imatinib sensitivity. Thus, alternate Bcr-Abl kinase inhibitors that have activity against imatinib-resistant mutants would be useful for patients who relapse on imatinib therapy. Two such Bcr-Abl inhibitors are currently being evaluated in clinical trials: the improved potency, selective Abl inhibitor AMN107 and the highly potent dual Src/Abl inhibitor BMS-354825. In the current article, we compared imatinib, AMN107, and BMS-354825 in cellular and biochemical assays against a panel of 16 kinase domain mutants representing >90% of clinical isolates. We report that AMN107 and BMS-354825 are 20-fold and 325-fold more potent than imatinib against cells expressing wild-type Bcr-Abl and that similar improvements are maintained for all imatinib-resistant mutants tested, with the exception of T315I. Thus, both inhibitors hold promise for treating imatinib-refractory CML.

Subfields: Genetics, Hematology, Rheumatology

View Paper: https://www.semanticscholar.org/paper/4a4ba81b5a8cab7d178b242d035ca904dd5fc518

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In Genetics

1. Zhesheng Chen
2. C. Ashby
3. J. Cortes
4. Andreas Hochhaus
5. H. Kantarjian
6. M. Baccarani
7. Brian J. Druker

In Hematology

1. J. Cortes
2. C. Ashby
3. Zhesheng Chen
4. J. Apperley
5. Andreas Hochhaus
6. J. Goldman
7. H. Kantarjian
8. M. Baccarani

In Rheumatology

1. J. Cortes
2. Andreas Hochhaus
3. H. Kantarjian
4. M. Baccarani
5. Brian J. Druker

Citations in the corpus

• The structure of Dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants. (2006, neutral): “cells expressing wild-type BCR-ABL (15).”
• BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: a review. (2010, background): “[43] O’Hare T, Walters DK, Stoffregen EP, Jia T, Manley PW, Mestan J, et al.”
• European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. (2013, background): “For bosutinib and ponatinib, IC50 values come from a single study each.(68,71) Plasma drug concentration is also given in nM.”