title: Scaffold hopping approach on the route to selective tankyrase inhibitors.
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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06123 Perugia, Italy; TES Pharma, Via P. Togliatti 22bis, 06073 Terrioli, Corciano, Italy.
authors.forename: Paride
authors.initials: P
authors.lastname: Liscio
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06123 Perugia, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Carotti
authors.affiliation: Icahn School of Medicine at Mount Sinai, Department of Oncological Sciences, 1425 Madison Ave, New York, NY 10029, USA.
authors.forename: Stefania
authors.initials: S
authors.lastname: Asciutti
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06123 Perugia, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Ferri
authors.affiliation: Icahn School of Medicine at Mount Sinai, Department of Oncological Sciences, 1425 Madison Ave, New York, NY 10029, USA.
authors.forename: Maira M
authors.initials: MM
authors.lastname: Pires
authors.affiliation: Icahn School of Medicine at Mount Sinai, Department of Oncological Sciences, 1425 Madison Ave, New York, NY 10029, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Valloscuro
authors.affiliation: Icahn School of Medicine at Mount Sinai, Department of Oncological Sciences, 1425 Madison Ave, New York, NY 10029, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Ziff
authors.affiliation: Icahn School of Medicine at Mount Sinai, Department of Pharmacology and Systems Therapeutics, 1425 Madison Ave, New York, NY 10029, USA.
authors.forename: Neil R
authors.initials: NR
authors.lastname: Clark
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06123 Perugia, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Macchiarulo
authors.affiliation: Icahn School of Medicine at Mount Sinai, Department of Oncological Sciences, 1425 Madison Ave, New York, NY 10029, USA.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Aaronson
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06123 Perugia, Italy; TES Pharma, Via P. Togliatti 22bis, 06073 Terrioli, Corciano, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Pellicciari
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06123 Perugia, Italy. Electronic address: emidio.camaioni@unipg.it.
authors.forename: Emidio
authors.initials: E
authors.lastname: Camaioni
mesh_terms: D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D021241:Spectrometry, Mass, Electrospray Ionization; D038501:Tankyrases / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D038501:Tankyrases
keywords: PARP family; Scaffold hopping; Tankyrase inhibitors; Virtual screening; Wnt disruption