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Structure-based design, synthesis and biological evaluation of a novel series of isoquinolone and pyrazolo[4,3-c]pyridine inhibitors of fascin 1 as potential anti-metastatic agents.

2019; Elsevier BV; Volume: 29; Issue: 8 Linguagem: Inglês

10.2210/pdb6i16/pdb

1464-3405

Stuart Francis, Daniel R. Croft, Alexander W. Schüttelkopf, Charles Parry, Angelo Pugliese, Ken Cameron, Sophie Claydon, Martin J. Drysdale, Claire Gardner, Andrea Gohlke, Gillian Goodwin, Christopher H. Gray, Jennifer Konczal, Laura McDonald, Mokdad Mezna, Andrew Pannifer, Nikki R. Paul, Laura M. Machesky, Heather J. McKinnon, Justin Bower,

Nanofabrication and Lithography Techniques

Fascin is an actin binding and bundling protein that is not expressed in normal epithelial tissues but overexpressed in a variety of invasive epithelial tumors. It has a critical role in cancer cell metastasis by promoting cell migration and invasion. Here we report the crystal structures of fascin in complex with a series of novel and potent inhibitors. Structure-based elaboration of these compounds enabled the development of a series with nanomolar affinities for fascin, good physicochemical properties and the ability to inhibit fascin-mediated bundling of filamentous actin. These compounds provide promising starting points for fascin-targeted anti-metastatic therapies.