WNT signaling plays paramount roles in organism development, physiology, and disease, representing a highly attractive target for drug development. However, no WNT-modulating drugs have been approved, with several candidates trudging through the early clinical trials. This delay instigates alternative approaches to discover WNT-modulating drugs. Natural products were the source of therapeutics for centuries, but the chemical diversity they offer, especially when looking at different taxonomic groups and habitats, is still to a large extent unexplored. These considerations urge researchers to screen natural compounds for the WNT-modulatory activities. Since several reviews on such endeavors exist, we here have attempted to present these efforts as "Land and sea tales" (citing the book title by Rudyard Kipling) superimposing them onto the traditional pipeline of drug discovery and early development. In doing so, we illustrate each step of the pipeline with case studies stemming from our own research. It will become obvious that several steps of the pipeline need to be modified when applied to natural products rather than to synthetic libraries. Yet the main message of this chapter is that natural compounds represent a powerful source for the WNT signaling modulators and can be developed towards drug candidates against WNT-dependent maladies.
