Zhao Yuguang, Ren Jingshan, Hillier James, Lu Weixian, Jones E Yvonne
Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom.
J Med Chem. 2020 Mar 26;63(6):3252-3260. doi: 10.1021/acs.jmedchem.9b02020. Epub 2020 Feb 25.
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.
Wnt信号通路的失调在人类癌症中很常见。开发针对Wnt受体卷曲蛋白（FZD）的小分子抑制剂可能在癌症治疗中具有潜力。在小分子筛选过程中，我们使用表面等离子体共振（SPR）观察到卡马西平与Wnt受体FZD8的富含半胱氨酸结构域（CRD）结合。细胞功能测定表明，卡马西平可抑制FZD8介导的Wnt/β-连环蛋白信号通路。我们以1.7 Å的分辨率确定了该复合物的晶体结构，结果显示卡马西平结合在FZD8 CRD上的一个新口袋中。独特的残基Tyr52使FZD8与密切相关的FZD5和其他FZDs在卡马西平结合方面有所区别。首个与小分子结合的FZD结构为抗FZD药物开发提供了基础。此外，观察到的卡马西平介导的Wnt信号抑制可能有助于解释一些患者在长期卡马西平治疗期间出现骨质流失和脂肪生成增加的现象。
