2. Academic Validation
  3. Scaffold hopping approach on the route to selective tankyrase inhibitors

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.
Paride Liscio 1,  Andrea Carotti 2,  Stefania Asciutti 3,  Martina Ferri 2,  Maira M Pires 3,  Sara Valloscuro 3,  Jacob Ziff 3,  Neil R Clark 4,  Antonio Macchiarulo 2,  Stuart A Aaronson 3,  Roberto Pellicciari 1,  Emidio Camaioni 5
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06123 Perugia, Italy; TES Pharma, Via P. Togliatti 22bis, 06073 Terrioli, Corciano, Italy.
  • 2 Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06123 Perugia, Italy.
  • 3 Icahn School of Medicine at Mount Sinai, Department of Oncological Sciences, 1425 Madison Ave, New York, NY 10029, USA.
  • 4 Icahn School of Medicine at Mount Sinai, Department of Pharmacology and Systems Therapeutics, 1425 Madison Ave, New York, NY 10029, USA.
  • 5 Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06123 Perugia, Italy. Electronic address: emidio.camaioni@unipg.it.
PMID: 25299683 DOI: 10.1016/j.ejmech.2014.10.007
Abstract

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.

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