Scaffold hopping approach on the route to selective tankyrase inhibitors

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...

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Published in:European journal of medicinal chemistry 2014-11, Vol.87, p.611-623
Main Authors: Liscio, Paride, Carotti, Andrea, Asciutti, Stefania, Ferri, Martina, Pires, Maira M., Valloscuro, Sara, Ziff, Jacob, Clark, Neil R., Macchiarulo, Antonio, Aaronson, Stuart A., Pellicciari, Roberto, Camaioni, Emidio
Format: Article
Language:English
Subjects:
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Magnetic Resonance Spectroscopy
Models, Molecular
PARP family
Scaffold hopping
Spectrometry, Mass, Electrospray Ionization
Tankyrase inhibitors
Tankyrases - antagonists & inhibitors
Virtual screening
Wnt disruption
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Summary: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. [Display omitted] •Methoxy[l]benzothieno[2,3-c]quinolin-6(5H)-one scaffold: a new hit as PARP inhibitor.•Structure-based and scaffold hopping approach in the discovery of new TNKS inhibitors.•New TNKS inhibitors: 2-phenyl-3H-benzo[4,5]thieno[3,2-d]pyrimidin-4-one derivatives.•2-Phenylbenzo[4,5]thieno[3,2-d]pyrimidin-4-one analogs as new Wnt pathway disruptors.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2014.10.007