Targeting Bcr–Abl by combining allosteric with ATP-binding-site inhibitors

Jianming Zhang, Francisco J. Adrián (), Wolfgang Jahnke, Sandra W. Cowan-Jacob, Allen G. Li, Roxana E. Iacob, Taebo Sim, John Powers, Christine Dierks, Fangxian Sun, Gui-Rong Guo, Qiang Ding, Barun Okram, Yongmun Choi, Amy Wojciechowski, Xianming Deng, Guoxun Liu, Gabriele Fendrich, André Strauss, Navratna Vajpai, Stephan Grzesiek, Tove Tuntland, Yi Liu, Badry Bursulaya, Mohammad Azam, Paul W. Manley, John R. Engen, George Q. Daley, Markus Warmuth () and Nathanael S. Gray ()
Additional contact information
Jianming Zhang: Dana-Farber Cancer Institute, Harvard Medical School, 250 Longwood Avenue, Seeley G. Mudd Building 628, Boston, Massachusetts 02115, USA
Francisco J. Adrián: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA
Wolfgang Jahnke: Novartis Institutes for Biomedical Research
Sandra W. Cowan-Jacob: Novartis Institutes for Biomedical Research
Allen G. Li: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA
Roxana E. Iacob: Northeastern University, Boston, Massachusetts 02115, USA
Taebo Sim: Dana-Farber Cancer Institute, Harvard Medical School, 250 Longwood Avenue, Seeley G. Mudd Building 628, Boston, Massachusetts 02115, USA
John Powers: Harvard Medical School; Howard Hughes Medical Institute; Boston, Massachusetts 02115, USA
Christine Dierks: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA
Fangxian Sun: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA
Gui-Rong Guo: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA
Qiang Ding: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA
Barun Okram: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Yongmun Choi: Dana-Farber Cancer Institute, Harvard Medical School, 250 Longwood Avenue, Seeley G. Mudd Building 628, Boston, Massachusetts 02115, USA
Amy Wojciechowski: Dana-Farber Cancer Institute, Harvard Medical School, 250 Longwood Avenue, Seeley G. Mudd Building 628, Boston, Massachusetts 02115, USA
Xianming Deng: Dana-Farber Cancer Institute, Harvard Medical School, 250 Longwood Avenue, Seeley G. Mudd Building 628, Boston, Massachusetts 02115, USA
Guoxun Liu: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA
Gabriele Fendrich: Novartis Institutes for Biomedical Research
André Strauss: Novartis Institutes for Biomedical Research
Navratna Vajpai: Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland
Stephan Grzesiek: Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland
Tove Tuntland: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA
Yi Liu: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA
Badry Bursulaya: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA
Mohammad Azam: Harvard Medical School; Howard Hughes Medical Institute; Boston, Massachusetts 02115, USA
Paul W. Manley: Novartis Institutes for Biomedical Research
John R. Engen: Northeastern University, Boston, Massachusetts 02115, USA
George Q. Daley: Harvard Medical School; Howard Hughes Medical Institute; Boston, Massachusetts 02115, USA
Markus Warmuth: Novartis Institutes for BioMedical Research, Inc., 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
Nathanael S. Gray: Dana-Farber Cancer Institute, Harvard Medical School, 250 Longwood Avenue, Seeley G. Mudd Building 628, Boston, Massachusetts 02115, USA

Nature, 2010, vol. 463, issue 7280, 501-506

Abstract: Abstract In an effort to find new pharmacological modalities to overcome resistance to ATP-binding-site inhibitors of Bcr–Abl, we recently reported the discovery of GNF-2, a selective allosteric Bcr–Abl inhibitor. Here, using solution NMR, X-ray crystallography, mutagenesis and hydrogen exchange mass spectrometry, we show that GNF-2 binds to the myristate-binding site of Abl, leading to changes in the structural dynamics of the ATP-binding site. GNF-5, an analogue of GNF-2 with improved pharmacokinetic properties, when used in combination with the ATP-competitive inhibitors imatinib or nilotinib, suppressed the emergence of resistance mutations in vitro, displayed additive inhibitory activity in biochemical and cellular assays against T315I mutant human Bcr–Abl and displayed in vivo efficacy against this recalcitrant mutant in a murine bone-marrow transplantation model. These results show that therapeutically relevant inhibition of Bcr–Abl activity can be achieved with inhibitors that bind to the myristate-binding site and that combining allosteric and ATP-competitive inhibitors can overcome resistance to either agent alone.

Date: 2010
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DOI: 10.1038/nature08675

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