3K5V

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

Zhang, J., Adrian, 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., Vajpai, N., Grzesiek, S., Tuntland, T., Liu, Y., Bursulaya, B., Azam, M., Manley, P.W., Engen, J.R., Daley, G.Q., Warmuth, M., Gray, N.S.

(2010) Nature 463: 501-506

• PubMed: 20072125 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1038/nature08675
• Primary Citation of Related Structures:  
  3K5V


• PubMed 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.

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Organizational Affiliation: 

Dana-Farber Cancer Institute, Harvard Medical School, Department of Cancer Biology, Seeley G. Mudd Building 628, Boston, Massachusetts 02115, USA.