Abstract：
The Frizzleds (FZDs) receptors on the cell surface belong to the class F of G protein-coupled receptors (GPCRs) which are the major receptors of WNT protein that mediates the classical WNT signaling pathway and other non-classical pathways. Besides, the FZDs also play a core role in tissue regeneration and tumor occurrence. With the structure and mechanism of FZDs activation becoming clearer, a series of FZDs modulators (inhibitors and agonists) have been developed, with the hope of bringing benefits to the treatment of cancer and degenerative diseases. Most of the FZDs inhibitors (small molecules, antibodies or designed protein inhibitors) block WNT signaling through binding to the cysteine-rich domain (CRD) of FZDs. Several small molecules impede FZDs activation by targeting to the third intracellular domain or the transmembrane domain of FZDs. However, three small molecules (FZM1.8, SAG1.3 and purmorphamine) activate the FZDs through direct interaction with the transmembrane domain. Another type of FZDs agonists are bivalent or tetravalent antibodies which activate the WNT signaling via inducing FZD-LRP5/6 heterodimerization. In this article, we reviewed the FZDs modulators reported in recent years, summarized the critical molecules\' discovery processes and the elucidated relevant structural and pharmacological mechanisms. We believe the summaried molecular mechanisms of the relevant modulators could provide important guidance and reference for the future development of FZD modulators.
摘要：
细胞表面上的Frizzleds（FZD）受体属于G蛋白偶联受体（GPCRs）的F类，是WNT蛋白的主要受体，介导经典的WNT信号传导途径和其他非经典途径。此外,FZDs在组织再生和肿瘤发生中也起着核心作用。随着FZDs活化的结构和机理越来越清晰,已经开发了一系列FZD调节剂（抑制剂和激动剂），希望为癌症和退行性疾病的治疗带来好处。大多数FZDs抑制剂（小分子，抗体或设计的蛋白质抑制剂）通过与FZD的富含半胱氨酸的结构域（CRD）结合来阻断WNT信号传导。若干小分子通过靶向FZD的第三胞内结构域或跨膜结构域来阻止FZD活化。然而,三个小分子（FZM1.8，SAG1.3和purmorphamine）通过与跨膜结构域的直接相互作用激活FZD。另一种类型的FZD激动剂是二价或四价抗体,其通过诱导FZD-LRP5/6异源二聚化激活WNT信号传导。在这篇文章中,我们回顾了近年来报道的FZDs调节剂，总结了关键分子的发现过程以及阐明的相关结构和药理机制。我们相信对相关调节剂分子机制的总结可为今后FZD调节剂的开发提供重要的指导和参考。
