Tankyrase Inhibitors (TNKS) 49 is a potent, selective and orally bioavailable inhibitor of tankyrase with IC50 value of 0.1nM [1].
Tankyrase 1 and tankyrase 2 are members of PARP family. They can use NAD+ as substrates to transfer ADP-ribose polymers onto tagert proteins. The tankyrase are found to bind to PARSylate axin proteins which are the negative regulator of Wnt pathway. It makes tankyrase to be targets in treatment for adenomatous polyposis coli. Tankyrase inhibitors 49 is an optimization of the previous hit compound inhibitor 8 with improved potency and selectivity. It has excellent effects in both tankyrase assay and cellular assay (total β-catenin degradation assay in SW480 cells) with IC50 values of 0.1nM and 1.9nM, respectively. In addition, it is found to be a dual binder with both the nicotinamide pocket and the induced pocket of the enzymes [1].
In the in vivo studies in rodents, tankyrase inhibitors 49 is found to potently inhibit TNKS2 autoparsylation with IC50 value of 7.6nM. It also causes stabilization and accumulation of axin protein in SW480 cells with EC50 value of 4nM. In DLD-1 cells with truncated APC, the inhibitor inhibits the STF reporter transcription with IC50 value of 0.3nM suggesting its downstream inhibitory activity on Wnt-associated transcription [1].
References:
[1] Hua Z, Bregman H, Buchanan J L, et al. Development of Novel Dual Binders as Potent, Selective, and Orally Bioavailable Tankyrase Inhibitors. Journal of medicinal chemistry, 2013, 56(24): 10003-10015.