Scaffold hopping approach on the route to selective tankyrase inhibitors

Paride Liscio, Andrea Carotti, Stefania Asciutti, Martina Ferri, Maira M. Pires, Sara Valloscuro, Jacob Ziff, Neil R. Clark, Antonio MacChiarulo, Stuart A. Aaronson, Roberto Pellicciari, Emidio Camaioni

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


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 Combining double low line 21 nM and TNKS-2 Combining double low line 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.

Original languageEnglish
Pages (from-to)611-623
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
StatePublished - 24 Nov 2014


  • PARP family
  • Scaffold hopping
  • Tankyrase inhibitors
  • Virtual screening
  • Wnt disruption


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