Small-Molecule Inhibitors of Tankyrases as Prospective Therapeutics for Cancer

Tankyrases are multifunctional poly­(adenosine
diphosphate-ribose)
polymerases that regulate diverse biological processes including telomere
maintenance and cellular signaling. These processes are often implicated
in a number of human diseases, with cancer being the most prevalent
example. Accordingly, tankyrase inhibitors have gained increasing
attention as potential therapeutics. Since the discovery of XAV939
and IWR-1 as the first tankyrase inhibitors over two decades ago,
tankyrase-targeted drug discovery has made significant progress. This
review starts with an introduction of tankyrases, with emphasis placed
on their cancer-related functions. Small-molecule inhibitors of tankyrases
are subsequently delineated based on their distinct modes of binding
to the enzymes. In addition to inhibitors that compete with oxidized
nicotinamide adenine dinucleotide (NAD+) for binding to
the catalytic domain of tankyrases, non-NAD+-competitive
inhibitors are detailed. This is followed by a description of three
clinically trialled tankyrase inhibitors. To conclude, some of challenges
and prospects in developing tankyrase-targeted cancer therapies are
discussed.