Structure-based design synthesis and biological evaluation of a novel series of isoquinolone and pyrazolo43-cpyridine inhibitors of fascin 1 as potential anti-metastatic agents

摘要

class="kwd-title">Keywords: Virtual screening, Fragments, Drug discovery, Medicinal chemistry, Cancer class="head no_bottom_margin" id="ab010title">AbstractFascin 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.