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.
- 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: [email protected].
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.