Comparison of the inhibition of tankyrase-2 by 2-aryl-7,8-dihydrothiopyrano[4,3-d]pyrimidin-4-ones and 2-aryl-5,6,7,8-tetrahydroquinazolin-4-ones

Tankyrase-1 (PARP-5a, TNKS-1, ARTD5) and tankyrase-2 (PARP-5b, TNKS-2, ARTD6) are members of the poly(ADP-ribose)polymerase (PARP) enzyme superfamily. They currently attract much interest owing to their roles at chromosomal telomeres, at the mitotic spindle and in the wnt signalling pathway, leading to identification as possible targets for drug design for cancer. XAV939 1a, 5-substituted-3-arylisoquinolin-1-ones 2, 2-arylquinazolin-4-ones 3 and 7-aryl-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-ones 4 have previously been identified as potent and selective inhibitors of the tankyrases.1-4 As part of an exploration of the structure-activity relationship around the core, short series of 2-aryl-7,8-dihydrothiopyrano[4,3-d]pyrimidin-4-ones 1 and 2-aryl-5,6,7,8-tetrahydroquinazolin-4-ones 5 were synthesised by condensation of the corresponding cyclic beta-keto esters with benzamidines. Both series of compounds inhibited tankyrase-2, although the 7,8-dihydrothiopyrano[4,3-d]pyrimidin-4-ones 1 were markedly more potent (IC50 8 – 38 nM) than the corresponding 5,6,7,8-tetrahydroquinazolin-4-ones 5 (IC50 172 – 560 nM). A modelling study showed that the two series of compounds bound to the nicotinamide-binding site of the enzyme in conformations with different puckers of the partly saturated rings. Our previous study showed that the tetrahydropyridine ring of 4 does adopt the favoured conformation on binding to tankyrase-2. The inability of the carbocyclic compounds to adopt the optimum conformation of the dihydrothiopyrano analogues upon binding may contribute to their lower potency. We thank Worldwide Cancer Research (formerly AICR) for part financial support.