Journal
MEDCHEMCOMM
Volume 6, Issue 9, Pages 1687-1692Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c5md00210a
Keywords
-
Funding
- Wellcome Trust, Seeding Drug Discovery Initiative (SDDI) [WT101816]
- Cancer Research UK [14532, 11566] Funding Source: researchfish
Ask authors/readers for more resources
The tankyrase proteins (TNKS, TNKS2), members of the PARP superfamily of enzymes, are attractive anticancer 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 similar to 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available