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

Zhang, Jianming and Adrián, Francisco J. and Jahnke, Wolfgang and Cowan-Jacob, Sandra W. and Li, Allen G. and Iacob, Roxana E. and Sim, Taebo and Powers, John and Dierks, Christine and Sun, Fangxian and Guo, Gui-Rong and Ding, Qiang and Okram, Barun and Choi, Yongmun and Wojciechowski, Amy and Deng, Xianming and Liu, Guoxun and Fendrich, Gabriele and Strauss, André and Vajpai, Navratna and Grzesiek, Stephan and Tuntland, Tove and Liu, Yi and Bursulaya, Badry and Azam, Mohammad and Manley, Paul W. and Engen, John R. and Daley, George Q. and Warmuth, Markus and Gray, Nathanael S.. (2010) Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature, Vol. 463, H. 7280. pp. 501-506.

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Official URL: http://edoc.unibas.ch/dok/A5840246

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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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Grzesiek)
UniBasel Contributors:Grzesiek, Stephan
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:08 Jun 2012 06:56
Deposited On:08 Jun 2012 06:49

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