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  • Discovery and characterization of a cell-permeable, small-molecule c-Abl kinase activator that binds to the myristoyl binding site.

Discovery and characterization of a cell-permeable, small-molecule c-Abl kinase activator that binds to the myristoyl binding site.

Chemistry & biology (2011-02-23)
Jingsong Yang, Nino Campobasso, Mangatt P Biju, Kelly Fisher, Xiao-Qing Pan, Josh Cottom, Sarah Galbraith, Thau Ho, Hong Zhang, Xuan Hong, Paris Ward, Glenn Hofmann, Brett Siegfried, Francesca Zappacosta, Yoshiaki Washio, Ping Cao, Junya Qu, Sophie Bertrand, Da-Yuan Wang, Martha S Head, Hu Li, Sheri Moores, Zhihong Lai, Kyung Johanson, George Burton, Connie Erickson-Miller, Graham Simpson, Peter Tummino, Robert A Copeland, Allen Oliff
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.

MATERIALS
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Product Description

Sigma-Aldrich
DPH, ≥98% (HPLC)