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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.

ABSTRACT: 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.

SUBMITTER: Francis S 

PROVIDER: S-EPMC6419574 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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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.

Francis Stuart S   Croft Daniel D   Schüttelkopf Alexander W AW   Parry Charles C   Pugliese Angelo A   Cameron Ken K   Claydon Sophie S   Drysdale Martin M   Gardner Claire C   Gohlke Andrea A   Goodwin Gillian G   Gray Christopher H CH   Konczal Jennifer J   McDonald Laura L   Mezna Mokdad M   Pannifer Andrew A   Paul Nikki R NR   Machesky Laura L   McKinnon Heather H   Bower Justin J  

Bioorganic & medicinal chemistry letters 20190130 8

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 p  ...[more]

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