3PYY

Discovery and Characterization of a Cell-Permeable, Small-Molecule c-Abl Kinase Activator that Binds to the Myristoyl Binding Site.

Yang, J., Campobasso, N., Biju, M.P., Fisher, K., Pan, X.Q., Cottom, J., Galbraith, S., Ho, T., Zhang, H., Hong, X., Ward, P., Hofmann, G., Siegfried, B., Zappacosta, F., Washio, Y., Cao, P., Qu, J., Bertrand, S., Wang, D.Y., Head, M.S., Li, H., Moores, S., Lai, Z., Johanson, K., Burton, G., Erickson-Miller, C., Simpson, G., Tummino, P., Copeland, R.A., Oliff, A.

(2011) Chem Biol 18: 177-186

• PubMed: 21338916 Search on PubMed
• DOI: https://doi.org/10.1016/j.chembiol.2010.12.013
• Primary Citation of Related Structures:  
  3PYY


• PubMed Abstract: 
  

  c-Abl kinase activity is regulated by a unique mechanism involving the formation of an autoinhibited conformation in which the N-terminal myristoyl group binds intramolecularly to the myristoyl binding site on the kinase domain and induces the bending of the αI helix that creates a docking surface for the SH2 domain. Here, we report a small-molecule c-Abl activator, DPH, that displays potent enzymatic and cellular activity in stimulating c-Abl activation. Structural analyses indicate that DPH binds to the myristoyl binding site and prevents the formation of the bent conformation of the αI helix through steric hindrance, a mode of action distinct from the previously identified allosteric c-Abl inhibitor, GNF-2, that also binds to the myristoyl binding site. DPH represents the first cell-permeable, small-molecule tool compound for c-Abl activation.

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Organizational Affiliation: 

Oncology Research and Development, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA. jingsong.2.yang@gsk.com