The antiepileptic drug carbamazepine binds to a novel pocket on the Wnt receptor Frizzled-8

Misregulation of Wnt signalling is common in human cancer. Development of small molecule inhibitors against the Wnt receptor, Frizzled (FZD), may have potential in cancer therapy. During small molecule screens, we observed binding of carbamazepine (CBZ) to the cysteine-rich domain (CRD) of the Wnt receptor FZD8 using surface plasmon resonance (SPR). Cellular functional assays demonstrated CBZ can suppress FZD8 mediated Wnt/β-catenin signalling. We determined the crystal structure of the complex at 1.7A resolution, which reveals that CBZ binds at a novel pocket on the FZD8 CRD. The unique residue Tyr52 discriminates FZD8 from the closely-related FZD5 and other FZDs for CBZ binding. The first small molecule-bound FZD structure provides a basis for anti-FZD drug development. Furthermore, the observed CBZ mediated Wnt signalling inhibition may help to explain the phenomenon of bone loss and increased adipogenesis in some patients during long-term CBZ treatment.