2. Academic Validation
  3. 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.
PMID: 30773430 DOI: 10.1016/j.bmcl.2019.01.035
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
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