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 & 10 others Stephan 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

371 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

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Adenosine Triphosphate
Binding Sites
Myristic Acid
X Ray Crystallography
Bone Marrow Transplantation
Mutagenesis
Hydrogen
Mass Spectrometry
Pharmacokinetics
Pharmacology
Mutation

ASJC Scopus subject areas

  • General

Cite this

Zhang, J., Adrián, F. J., Jahnke, W., Cowan-Jacob, S. W., Li, A. G., Iacob, R. E., ... 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

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

In: Nature, Vol. 463, No. 7280, 28.01.2010, p. 501-506.

Research output: Contribution to journalArticle

Zhang, J, Adrián, FJ, Jahnke, W, Cowan-Jacob, SW, Li, AG, Iacob, RE, Sim, T, Powers, J, Dierks, C, Sun, F, Guo, GR, Ding, Q, Okram, B, Choi, Y, Wojciechowski, A, Deng, X, Liu, G, Fendrich, G, Strauss, A, Vajpai, N, Grzesiek, S, Tuntland, T, Liu, Y, Bursulaya, B, Azam, M, Manley, PW, Engen, JR, Daley, GQ, Warmuth, M & Gray, NS 2010, 'Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors', Nature, vol. 463, no. 7280, pp. 501-506. https://doi.org/10.1038/nature08675
Zhang J, Adrián FJ, Jahnke W, Cowan-Jacob SW, Li AG, Iacob RE et al. Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature. 2010 Jan 28;463(7280):501-506. https://doi.org/10.1038/nature08675
Zhang, Jianming ; Adrián, Francisco J. ; Jahnke, Wolfgang ; Cowan-Jacob, Sandra W. ; Li, Allen G. ; Iacob, Roxana E. ; Sim, Taebo ; Powers, John ; Dierks, Christine ; Sun, Fangxian ; Guo, Gui Rong ; Ding, Qiang ; Okram, Barun ; Choi, Yongmun ; Wojciechowski, Amy ; Deng, Xianming ; Liu, Guoxun ; Fendrich, Gabriele ; Strauss, André ; Vajpai, Navratna ; Grzesiek, Stephan ; Tuntland, Tove ; Liu, Yi ; Bursulaya, Badry ; Azam, Mohammad ; Manley, Paul W. ; Engen, John R. ; Daley, George Q. ; Warmuth, Markus ; Gray, Nathanael S. / Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. In: Nature. 2010 ; Vol. 463, No. 7280. pp. 501-506.
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