Small-Molecule Inhibitors of Tankyrases as Prospective Therapeutics for Cancer

Tankyrases are multifunctional poly(adenosine diphosphate-ribose) polymerases that regulate diverse biologicalprocesses including telomere maintenance and cellular signaling. These processes are often implicated in a number of humandiseases, with cancer being the most prevalent example. Accordingly, tankyrase inhibitors have gained increasing attention aspotential therapeutics. Since the discovery of XAV939 and IWR-1 as thefirst 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 ontheir cancer-related functions. Small-molecule inhibitors of tankyrases are subsequently delineated based on their distinct modes ofbinding to the enzymes. In addition to inhibitors that compete with oxidized nicotinamide adenine dinucleotide (NAD+) for bindingto the catalytic domain of tankyrases, non-NAD+-competitive inhibitors are detailed. This is followed by a description of threeclinically trialled tankyrase inhibitors. To conclude, some of challenges and prospects in developing tankyrase-targeted cancertherapies are discussed.