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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

DOI: 10.1016/j.bmcl.2019.01.035 DOI Help

Authors: Stuart Francis (CRUK Beatson Institute) , Daniel Croft (CRUK Beatson Institute) , Alexander W. Schuettelkopf (CRUK Beatson Institute) , Charles Parry (CRUK Beatson Institute) , Angelo Pugliese (CRUK Beatson Institute) , Ken Cameron (CRUK Beatson Institute) , Sophie Claydon (CRUK Beatson Institute) , Martin Drysdale (CRUK Beatson Institute) , Claire Gardner (CRUK Beatson Institute) , Andrea Gohlke (CRUK Beatson Institute) , Gillian Goodwin (CRUK Beatson Institute) , Christopher H. Gray (CRUK Beatson Institute) , Jennifer Konczal (CRUK Beatson Institute) , Laura Mcdonald (CRUK Beatson Institute) , Mokdad Mezna (CRUK Beatson Institute) , Andrew Pannifer (CRUK Beatson Institute) , Nikki Paul (CRUK Beatson Institute) , Laura Machesky (CRUK Beatson Institute; University of Glasgow) , Heather Mckinnon (CRUK Beatson Institute) , Justin Bower (CRUK Beatson Institute)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Bioorganic & Medicinal Chemistry Letters

State: Published (Approved)
Published: January 2019
Diamond Proposal Number(s): 6683 , 8659 , 11651

Open Access Open Access

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. Subsequent structure-based elaboration of this and related 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.

Journal Keywords: virtual screening; fragments; drug discovery; medicinal chemistry; cancer

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Documents:
1-s2.0-S0960894X19300563-main.pdf