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, S. et al. (2019) 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. Bioorganic and Medicinal Chemistry Letters, 29(8), pp. 1023-1029. (doi: 10.1016/j.bmcl.2019.01.035) (PMID:30773430) (PMCID:PMC6419574)

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.

• Item Type: Articles
• Additional Information: This research was supported by funding from Cancer Research UK (grants A17196 and A17096) and the Pancreatic Cancer Research Fund.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Croft, Dr Daniel and Pugliese, Dr Angelo and Claydon, Sophie and Drysdale, Dr Martin and Bower, Professor Justin and Cameron, Mr Ken and Pannifer, Dr Andrew and Machesky, Professor Laura and Mezna, Dr Mokdad and Gray, Dr Christopher and Parry, Mr Charles and McDonald, Dr Laura and Goodwin, Mrs Gillian and Francis, Mr Stuart
• Authors: Francis, S., Croft, D., Schüttelkopf, A. W., Parry, C., Pugliese, A., Cameron, K., Claydon, S., Drysdale, M., Gardner, C., Gohlke, A., Goodwin, G., Gray, C., Konczal, J., McDonald, L., Mezna, M., Pannifer, A., Paul, N. R., Machesky, L., McKinnon, H., and Bower, J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Bioorganic and Medicinal Chemistry Letters
• Publisher: Elsevier
• ISSN: 0960-894X
• ISSN (Online): 0960-894X
• Published Online: 30 January 2019
• Copyright Holders: Copyright © 2019 The Authors
• First Published: First published in Bioorganic and Medicinal Chemistry Letters 29(8):1023-1029
• Publisher Policy: Reproduced under a Creative Commons License