Platforms for high-throughput screening of Wnt/Frizzled antagonists

Signaling cascades initiated by Wnt lipoglycoproteins and their receptors of the Frizzled family regulate many aspects of animal development and physiology. Improper activation of this signaling promotes carcinogenic transformation and metastasis. Development of agents blocking the Wnt-Frizzled signaling is of prime interest for drug discovery. Despite certain progress no such agents are as yet brought to the market or even to clinical trials. One reason for these delays might be the use of suboptimal readout assays. In this article we overview existing and developing assay platforms to screen for Wnt-Frizzled antagonists. Among those, G protein-activating assays built on the emerging GPCR properties of Frizzleds are highlighted.

► No anticancer therapies targeting the Wnt-FZD pathway exist despite urgent need.
► Currently transcription-based readouts dominate as the screening platform.
► Assays focusing on earlier events in Wnt-FZD signaling may be required.
► We overview existing and developing platforms for Wnt-FZD antagonist screening.
► The new platforms are based on the emerging GPCR properties of FZD proteins.