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Discovery and SAR of [1,2,4]triazol-3-ylsulfanylmethyl)-3-phenyl-[1,2,4]oxadiazoles: Antagonists of the Wnt pathway that inhibit tankyrase 1&2

Shultz, Michael, Kirby, Christina, Stams, Travis, Chin, Donovan, Blank, Jutta, Charlat, Olga, Cheng, Hong, Cheung, Atwood, Feng, Yun, Fortin, Pascal, Hood, Tami, Tyagi, Viraj, Xu, Ming, Zhang, Bailin and Shao, Wenlin (2012) Discovery and SAR of [1,2,4]triazol-3-ylsulfanylmethyl)-3-phenyl-[1,2,4]oxadiazoles: Antagonists of the Wnt pathway that inhibit tankyrase 1&2. Journal of Medicinal Chemistry, 55 (3). pp. 1127-1136. ISSN 0022-2623


The Wnt signaling pathway is 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 molecule modulators of Wnt signaling has proven challenging, largely due to the relative paucity of druggable nodes in this pathway. Several recent publications have identified small molecule inhibitors of the Wnt pathway and tankyrase (TNKS) inhibition has been demonstrated to antagonize Wnt signaling via axin stabilization. Herein we report the early hit assessment of a series of compounds previously reported to antagonize Wnt 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]oxadiazole inhibitors of TNKS1 and 2. Furthermore, a co-crystal structure of compound 24 complexed to TNKS1 demonstrates an alternate binding mode for PARP family member proteins that does not involve interactions with the nicotinamide binding pocket.

Item Type: Article
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15


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