Tankyrases (TNKSs), members of the PARP (Poly(ADP-ribose)polymerases) superfamily of enzymes, have
gained interest as therapeutic drug targets, especially as they are involved in the regulation of Wnt
signalling. A series of 2-arylquinazolin-4-ones with varying substituents at the 8-position was synthesised.
An 8-methyl group (compared to 8-H, 8-OMe, 8-OH), together with a 40-hydrophobic or
electron-withdrawing group, provided the most potency and selectivity towards TNKSs. Co-crystal
structures of selected compounds with TNKS-2 revealed that the protein around the 8-position is
more hydrophobic in TNKS-2 compared to PARP-1/2, rationalising the selectivity. The NADþ-binding site
contains a hydrophobic cavity which accommodates the 2-aryl group; in TNKS-2, this has a tunnel to the exterior but the cavity is closed in PARP-1. 8-Methyl-2-(4-trifluoromethylphenyl)quinazolin-4-one was identified as a potent and selective inhibitor of TNKSs and Wnt signalling. This compound and analogues could serve as molecular probes to study proliferative signalling and for development of inhibitors of TNKSs as drugs.