Antiepileptic Drug Carbamazepine Binds to a Novel Pocket on the Wnt Receptor Frizzled-8

Abstract

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

Targeting the Wnt/β-catenin signaling pathway in cancer

“…F2.A suppresses pancreatic cancer tumor growth in xenograft mouse models. Interestingly, carbamazepine, an antiepileptic drug, was recently reported to bind the cysteine-rich domain of FZD8, which suggests been explored as a promising therapy option in cancers [48]. Additionally, Fz7-21, a selective FZD7-binding peptide, disrupts intestinal stem cells and organoids, implicating the potential of therapeutic application in malignant diseases [49].…”

“…In addition, researchers had found some old drugs performed new tricks, which play important roles in tumor growth, invasion and metastasis via regulating Wnt/β-catenin signaling pathway. Carbamazepine, an antiepileptic drug, was recently reported to bind the cysteine-rich domain of FZD8, which suggested to been explored as a promising therapy option in cancers [48]. It was also reported that psychiatric agent hexachlorophene attenuated Wnt/β-catenin signaling through suppressing β-catenin degradation in colon cancer cells [111].…”

Wnt Signaling in Gynecologic Malignancies

“…FA.2 inhibits pancreatic cancer tumor growth in xenograft models [128], but this inhibitor has also not been tested in gynecologic malignancies. Carbamazapine, an antiepileptic drug, has recently been found to bind the cysteine-rich domain (CRD) of FZD8 [130]. Carbamazapine, an antiepileptic drug, has recently been found to bind the cysteine-rich domain (CRD) of FZD8 [130], suggesting that carbamazapine may be worth exploration as a treatment in gynecologic malignancies.…”

Non-Coding RNA and Frizzled Receptors in Cancer

“…Targeting non-coding RNAs present an additional approach to inhibiting oncogenic pathways or enhancing tumor-suppressive pathways. Challenges of targeting Fzds include lack of high-resolution crystal structures for Fzds and context-dependent associations of individual Wnts and Fzds ( Schulte and Kozielewicz, 2020 ; Zhao et al, 2020 ). Using non-coding RNA to target Fzd activity could circumvent some of these challenges by altering expression, instead of attempting to bind to Fzd receptors or by offering tissue- or disease-specific targeting.…”

“…For instance, compounds that bind to the transmembrane domain of Fzd7 and interfere with Wnt binding could reduce oncogenic signaling in many cancer types ( Kalhor et al, 2020 ). The epilepsy drug carbamazepine binds Fzd8 to suppress β-catenin signaling ( Zhao et al, 2020 ), and Fzd9 may be a critical receptor for a lung cancer chemoprevention drug ( Tennis et al, 2010 ). Identifying non-coding RNAs that enhance or inhibit downstream Fzd signaling will support new approaches to cancer prevention and treatment.…”