WNT signaling is frequently deregulated in malignancy, particularly in colon cancer, and plays a key role in the generation and maintenance of cancer stem cells. Here we report the discovery and optimization of an indazole series identified from an HTS screen on a defined biochemical target with activity on a cell-based reporter assay of the WNT pathway. We disclose X-ray co-crystal structures with the biochemical target and medicinal chemistry optimization to increase potency, improve physicochemical properties and oral pharmacokinetics. In addition, the selectivity and off-target profiles will be shown. Evidence for <i>in vivo</i> activity after oral dosing in a solid human tumor xenograft model will be demonstrated.

Wnt pathway inhibitors – indazoles

250th National Meeting (2015)

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