Discovery and characterization of a cell-permeable, small-molecule c-Abl kinase activator that binds to the myristoyl binding site |
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Authors: | 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 |
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Institution: | Oncology Research and Development, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA. jingsong.2.yang@gsk.com |
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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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