[1,2,4]triazol-3-ylsulfanylmethyl)-3-phenyl-[1,2,4]oxadiazoles: antagonists of the Wnt pathway that inhibit tankyrases 1 and 2 via novel adenosine pocket binding.

The Wnt signaling pathwayis critical to the regulation of key cellular processes. When deregulated, it has been shown to play a crucial role in the growth and progression of multiple human cancers. The identification of small moleculemodulators of Wnt signaling has proven challenging, largely due to the relative paucity of druggablenodes in this pathway. Several recent publications have identified small moleculeinhibitors of the Wnt pathway, and tankyrase (TNKS) inhibition has been demonstrated to antagonizeWnt signaling via axin stabilization. Herein, we report the early hit assessment of a series of compounds previously reported to antagonizeWnt signaling. We report the biophysical, computational characterization, structure–activity relationship, and physicochemical properties of a novel series of [ 1,2,4]triazol-3-ylsulfanylmethyl)-3-phenyl-[1,2,4] oxadiazoleinhibitors of TNKS1 and 2. Furthermore, a cocrystalstructure of compound 24 complexed to TNKS1 demonstrates an alternate binding mode for PA...