484049-04-9Relevant articles and documents
Discovery and characterization of a cell-permeable, small-molecule c-Abl kinase activator that binds to the myristoyl binding site
Yang, Jingsong,Campobasso, Nino,Biju, Mangatt P.,Fisher, Kelly,Pan, Xiao-Qing,Cottom, Josh,Galbraith, Sarah,Ho, Thau,Zhang, Hong,Hong, Xuan,Ward, Paris,Hofmann, Glenn,Siegfried, Brett,Zappacosta, Francesca,Washio, Yoshiaki,Cao, Ping,Qu, Junya,Bertrand, Sophie,Wang, Da-Yuan,Head, Martha S.,Li, Hu,Moores, Sheri,Lai, Zhihong,Johanson, Kyung,Burton, George,Erickson-Miller, Connie,Simpson, Graham,Tummino, Peter,Copeland, Robert A.,Oliff, Allen
, p. 177 - 186 (2011)
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.
