Frizzleds as dynamic, pharmacological and druggable entities

Diverse signaling systems are attractive targets for anti-cancer therapy, one of which is the WNT/Frizzled signaling system, where secreted WNT proteins activate Frizzled receptors driving cancer cell proliferation, migration and invasion.

The WNT/Frizzled signaling systems is of particular interest in pancreatic cancer carrying a mutation in the gene RNF43, which directly amplifies FZD signaling.

This opens the opportunity for a precision medicine approach and our recent work on the first small molecules inhibiting Frizzleds validates this hypothesis.My research team has investigated Frizzled transduction mechanisms for more than fifteen years and our recent progress in pharmacology and structural biology (cryogenic electron microscopy, CryoEM), enables us now to understand molecular details of FZD activation, how they contribute to oncogenesis and how they can be targeted pharmacologically.

In a combined biochemical, pharmacological and biophysical approach, we will further detail mechanisms of receptor activation, pathway initiation and signal specification to engage in a mechanism-based and structure-guided drug discovery process.

The combination of receptor pharmacology, novel genetically encoded biosensors, in silico ligand docking, molecular dynamics simulations and a structure-based approach aiming to obtain high resolution information of Frizzleds in complex with ligands or intracellular binding proteins will provide novel insights into FZDs as a drug target.