The tankyrases are members of the PARP superfamily; they poly(ADP-ribosyl)ate their target proteins
using NAD+ as a source of electrophilic ADP-ribosyl units. The three principal protein substrates of the
tankyrases (TRF1, NuMA and axin) are involved in replication of cancer cells; thus inhibitors of the tankyrases
may have anticancer activity. Using structure-based drug design and by analogy with known 3-
arylisoquinolin-1-one and 2-arylquinazolin-4-one inhibitors, series of arylnaphthyridinones,
arylpyridinopyrimidinones and their tetrahydro-derivatives were synthesised and evaluated in vitro.
7-Aryl-1,6-naphthyridin-5-ones, 3-aryl-2,6-naphthyridin-1-ones and 3-aryl-2,7-naphthyridin-1-ones
were prepared by acid-catalysed cyclisation of the corresponding arylethynylpyridinenitriles or
reaction of bromopyridinecarboxylic acids with b-diketones, followed by treatment with NH3. The
7-aryl-1,6-naphthyridin-5-ones were methylated at 1-N and reduced to 7-aryl-1-methyl-1,2,3,4-tetrahydro-
1,6-naphthyridin-5-ones. Cu-catalysed reaction of benzamidines with bromopyridinecarboxylic
acids furnished 2-arylpyrido[2,3-d]pyrimidin-4-ones. Condensation of benzamidines with methyl
1-benzyl-4-oxopiperidine-3-carboxylate and deprotection gave 2-aryl-5,6,7,8-tetrahydropyrido[4,3-
d]pyrimidin-4-ones, aza analogues of the known inhibitor XAV939. Introduction of the ring-N in the
arylnaphthyridinones and the arylpyridopyrimidinones caused >1000-fold loss in activity, compared
with their carbocyclic isoquinolinone and quinazolinone analogues. However, the 7-aryl-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-ones showed excellent inhibition of the tankyrases, with some examples having IC50 = 2 nM. One compound (7-(4-bromophenyl)-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-one) showed 70-fold selectivity for inhibition of tankyrase-2 versus tankyrase-1. The mode of binding was explored through crystal structures of inhibitors in complex with tankyrase-2.