Tankyrases (TNKS) cleave NAD+ to produce nicotinamide and ADP-ribose, which is then covalently attached to an acceptor protein in the process known as poly(ADP-ribosyl)ation. WIKI4 is a potent and selective inhibitor of TNKS1 and TNKS2 (IC50s = 26 and 15 nM, respectively). It has little or no effect on related polymerases or transferases at 10 μM. Through its effects on TNKS2, WIKI4 prevents AXIN ubiquitinylation and degradation, blocking signaling through the Wnt/β-catenin pathway. WIKI4 inhibits the expression of β-catenin target genes and cellular responses to Wnt/β-catenin signaling in both cancer cell lines and embryonic stem cells.
