TY - JOUR
T1 - Design and discovery of 3-aryl-5-substituted-isoquinolin-1-ones as potent tankyrase inhibitors
AU - Elliott, Richard J. R.
AU - Jarvis, Ashley
AU - Rajasekaran, Mohan B.
AU - Menon, Malini
AU - Bowers, Leandra
AU - Boffey, Ray
AU - Bayford, Melanie
AU - Firth-Clark, Stuart
AU - Key, Rebekah
AU - Aqil, Rehan
AU - Kirton, Stewart B.
AU - Niculescu-Duvaz, Dan
AU - Fish, Laura
AU - Lopes, Filipa
AU - McLeary, Robert
AU - Trindade, Ines
AU - Vendrell, Elisenda
AU - Munkonge, Felix
AU - Porter, Rod
AU - Perrior, Trevor
AU - Springer, Caroline
AU - Oliver, Antony W.
AU - Pearl, Laurence H.
AU - Ashworth, Alan
AU - Lord, Christopher J.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
U2 - 10.1039/C5MD00210A
DO - 10.1039/C5MD00210A
M3 - Article
SN - 2040-2503
VL - 6
SP - 1687
EP - 1692
JO - MedChemComm
JF - MedChemComm
IS - 9
ER -
