Dataset Information

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.

SUBMITTER: Liscio P

PROVIDER: S-EPMC4415586 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Scaffold hopping approach on the route to selective tankyrase inhibitors.

Liscio Paride P Carotti Andrea A Asciutti Stefania S Ferri Martina M Pires Maira M MM Valloscuro Sara S Ziff Jacob J Clark Neil R NR Macchiarulo Antonio A Aaronson Stuart A SA Pellicciari Roberto R Camaioni Emidio E

European journal of medicinal chemistry 20141005

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 ...[more]

PMID: 25299683

Dataset Information

Scaffold hopping approach on the route to selective tankyrase inhibitors.

Publications

Scaffold hopping approach on the route to selective tankyrase inhibitors.

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