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Small Molecules Inspired by the Natural Product Withanolides as Potent Inhibitors of Wnt Signaling

Wnt signaling is a fundamental pathway that drives embryonic development and is essential for stem cell maintenance and tissue homeostasis. Dysregulation of Wnt signaling is linked to various diseases, and a constitutively active Wnt pathway drives tumorigenesis. Thus, disruption of the Wnt response is deemed a promising strategy for cancer drug discovery. However, only few clinical drug candidates that target Wnt signaling are available so far, and new small‐molecule modulators of Wnt‐related processes are in high demand. Here we describe the synthesis of small molecules inspired by withanolide natural products by using a pregnenolone‐derived β‐lactone as the key intermediate that was transformed into a δ‐lactone appended to the D‐ring of the steroidal scaffold. This natural‐product‐inspired compound library contained potent inhibitors of Wnt signaling that act upstream of the destruction complex to stabilize Axin in a tankyrase‐independent manner.