Scaffold hopping approach on the route to selective tankyrase inhibitors

Eur J Med Chem. 2014 Nov 24;87:611-23. doi: 10.1016/j.ejmech.2014.10.007. Epub 2014 Oct 5.


A virtual screening procedure was applied to identify new tankyrase inhibitors. Through pharmacophore screening of a compounds collection from the SPECS database, the methoxy[l]benzothieno[2,3-c]quinolin-6(5H)-one scaffold was identified as nicotinamide mimetic able to inhibit tankyrase activity at low micromolar concentration. In order to improve potency and selectivity, tandem structure-based and scaffold hopping approaches were carried out over the new scaffold leading to the discovery of the 2-(phenyl)-3H-benzo[4,5]thieno[3,2-d]pyrimidin-4-one as powerful chemotype suitable for tankyrase inhibition. The best compound 2-(4-tert-butyl-phenyl)-3H-benzo[4,5]thieno[3,2-d]pyrimidin-4-one (23) displayed nanomolar potencies (IC50s TNKS-1 = 21 nM and TNKS-2 = 29 nM) and high selectivity when profiled against several other PARPs. Furthermore, a striking Wnt signaling, as well as cell growth inhibition, was observed assaying 23 in DLD-1 cancer cells.

Keywords: PARP family; Scaffold hopping; Tankyrase inhibitors; Virtual screening; Wnt disruption.

MeSH terms

  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Spectrometry, Mass, Electrospray Ionization
  • Tankyrases / antagonists & inhibitors*


  • Enzyme Inhibitors
  • Tankyrases