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Description

A cell-permeable dihydrothiopyranopyrimidinol that binds TNKS1/PARP5a and TNKS2/PARP5b with high affinity (Kd = 99 and 93 nM, respectively) and potently inhibits their PARsylation (poly ADP-ribosylation) activity (IC50 = 11 and 4 nM, respectively), while exhibiting much lower activity against PARP1 and PARP2 (IC50 = 2.194 and 0.114 microM, respectively). TNKS, but not PARP1/2, function knockdown by siRNA or XAV939 treatment suppresses cellular axin1/2 PARsylation and ubiquitination/proteasomal degradation, resulting in axin build-up, &beta,-catenin destruction, and blockage of Wnt signaling. XAV939 is shown to inhibit the growth of &beta,-catenin-dependent DLD-1, but not that of &beta,-catenin-independent RKO, cells (by >95% vs. no effect at 3.3 microM, respectively) in vitro and prevent the regeneration of zebrafish tail fin (by ~70% at 7 d post-amputation, 5 microM) after surgical removal in vivo.