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. Epub 2019 Jan 30.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / metabolism
  • Binding Sites
  • Carrier Proteins / antagonists & inhibitors*
  • Carrier Proteins / metabolism
  • Crystallography, X-Ray
  • Drug Design*
  • Humans
  • Inhibitory Concentration 50
  • Microfilament Proteins / antagonists & inhibitors*
  • Microfilament Proteins / metabolism
  • Molecular Docking Simulation
  • Protein Structure, Tertiary
  • Pyrazoles / chemistry*
  • Pyrazoles / metabolism
  • Pyridines / chemistry*
  • Pyridines / metabolism
  • Quinolones / chemistry*
  • Quinolones / metabolism
  • Structure-Activity Relationship


  • Antineoplastic Agents
  • Carrier Proteins
  • FSCN1 protein, human
  • Microfilament Proteins
  • Pyrazoles
  • Pyridines
  • Quinolones
  • pyrazolopyridine