Synthesis of novel inhibitors blocking Wnt signaling downstream of β-Catenin

► We developed an easy method to synthesize novel Wnt inhibitors based on the structure of haloquinone. ► This allows to design novel inhibitors simply by modifying the functional groups at the backbone. ► Two compounds inhibit Wnt/β-Catenin signaling in two independent bona fide Wnt-activity assays. ► The new inhibitors block endogenous Wnt-driven transcription. ► Symmetrical compounds act as Wnt antagonists, asymmetrical compounds do not.