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
  • 1. Drug Discovery Unit, CRUK Beatson Institute, Glasgow G61 1BD, UK. Electronic address: [email protected].
  • 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.
Products