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

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• 作者：Jingsong Yang¹ ; ^{jingsong.2.yang@gsk.com} ; Nino Campobasso² ; Mangatt P. Biju¹ ; Kelly Fisher¹ ; Xiao-Qing Pan¹ ; Josh Cottom² ; Sarah Galbraith¹ ; Thau Ho² ; Hong Zhang² ; Xuan Hong² ; Paris Ward² ; Glenn Hofmann² ; Brett Siegfried² ; Francesca Zappacosta² ; Yoshiaki Washio² ; Ping Cao² ; Junya Qu² ; Sophie Bertrand² ; Da-Yuan Wang² ; Martha S. Head² ; Hu Li² ; Sheri Moores¹ ; Zhihong Lai¹ ; Kyung Johanson² ; George Burton² ; Connie Erickson-Miller¹ ; Graham Simpson² ; Peter Tummino¹ ; Robert A. Copeland¹ ; Allen Oliff¹ ; ²
• 刊名：Chemistry & Biology
• 出版年：2011
• 出版时间：25 February 2011
• 年：2011
• 卷：18
• 期：2
• 页码：177-186
• 全文大小：960 K

文摘

Summary

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.