Design and discovery of 3-aryl-5-substituted-isoquinolin-1-ones as potent tankyrase inhibitors
| Autor: | Antony W. Oliver, Dan Niculescu-Duvaz, Melanie Jayne Bayford, Elisenda Vendrell, Christopher J. Lord, Alan Ashworth, Ashley Jarvis, Rebekah Elisabeth Key, Laurence H. Pearl, Stuart Firth-Clark, Malini Menon, Richard Elliott, Mohan B. Rajasekaran, Raymond John Boffey, Filipa Lopes, Leandra Bowers, Rehan Aqil, Ines Trindade, Caroline J. Springer, Stewart B. Kirton, Trevor Perrior, Felix Munkonge, Rod Porter, Laura Fish, Robert McLeary |
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| Rok vydání: | 2015 |
| Předmět: |
Pharmacology
chemistry.chemical_classification In silico Organic Chemistry Cell Pharmaceutical Science Biology Biochemistry Small molecule Molecular biology In vitro chemistry.chemical_compound medicine.anatomical_structure Enzyme chemistry Drug Discovery medicine Molecular Medicine Homology modeling Pharmacophore Growth inhibition |
| Zdroj: | MedChemComm. 6:1687-1692 |
| ISSN: | 2040-2511 2040-2503 |
| DOI: | 10.1039/c5md00210a |
| Popis: | The tankyrase proteins (TNKS, TNKS2), members of the PARP superfamily of enzymes, are attractive anti-cancer drug targets, particularly as inhibition of their catalytic activity has been shown to antagonise oncogenic WNT signalling. To identify chemical inhibitors of tankyrase we carried out an in silico small molecule screen using a set of ‘PARP-binding’ pharmacophores together with a generated (liganded) tankyrase homology model. This approach identified a structurally diverse set of ~1000 compounds for further study. Subsequent in vitro screening of recombinant tankyrase protein identified a subset of 59 confirmed inhibitors. Early optimisation followed by cell-based studies in WNT-dependent tumour cells, as well as co-crystallisation studies, identified a novel class of 3-aryl-5-substituted isoquinolin-1-ones, such as 21, that exhibit potent inhibition of tankyrase activity as well as growth inhibition of colorectal cancer cells. |
| Databáze: | OpenAIRE |
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