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 VajpaiStephan Grzesiek, Tove Tuntland, Yi Liu, Badry Bursulaya, Mohammad Azam, Paul W. Manley, John R. Engen, George Q. Daley, Markus Warmuth, Nathanael S. Gray

Research output: Contribution to journalArticle

396 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)501-506
Number of pages6
JournalNature
Volume463
Issue number7280
DOIs
Publication statusPublished - 2010 Jan 28

ASJC Scopus subject areas

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    Zhang, J., Adrián, F. J., Jahnke, W., Cowan-Jacob, S. W., Li, A. G., Iacob, R. E., Sim, T., Powers, J., Dierks, C., Sun, F., Guo, G. R., Ding, Q., Okram, B., Choi, Y., Wojciechowski, A., Deng, X., Liu, G., Fendrich, G., Strauss, A., ... Gray, N. S. (2010). Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature, 463(7280), 501-506. https://doi.org/10.1038/nature08675