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  2. 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

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

  • Bioorg Med Chem Lett. 2019 Apr 15;29(8):1023-1029. doi: 10.1016/j.bmcl.2019.01.035.
Stuart Francis 1 Daniel Croft 2 Alexander W Schüttelkopf 2 Charles Parry 2 Angelo Pugliese 2 Ken Cameron 2 Sophie Claydon 2 Martin Drysdale 2 Claire Gardner 2 Andrea Gohlke 2 Gillian Goodwin 2 Christopher H Gray 2 Jennifer Konczal 2 Laura McDonald 2 Mokdad Mezna 2 Andrew Pannifer 2 Nikki R Paul 3 Laura Machesky 4 Heather McKinnon 2 Justin Bower 2
Affiliations

Affiliations

  • 1 Drug Discovery Unit, CRUK Beatson Institute, Glasgow G61 1BD, UK. Electronic address: s.francis@beatson.gla.ac.uk.
  • 2 Drug Discovery Unit, CRUK Beatson Institute, Glasgow G61 1BD, UK.
  • 3 Cell Migration Laboratory, CRUK Beatson Institute, Glasgow G61 1BD, UK.
  • 4 Cell Migration Laboratory, CRUK Beatson Institute, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, G61 1QH Glasgow, UK.
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.

Keywords

Cancer; Drug discovery; Fragments; Medicinal chemistry; Virtual screening.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-111578
    99.87%, Fascin 1 抑制剂