The WNT pathway interconnects a network of signaling events involved in a huge plethora of cellular processes, from organogenesis to tissue homeostasis. Despite its importance, the exiguity of organic drugs directly targeting the members of the Frizzled family of WNT receptors has hampered progress across the whole spectrum of biological fields in which the signaling is involved. We here present FzM1.8, a small molecule acting as an allosteric agonist of Frizzled receptor FZD4. FzM1.8 derives from FzM1, a negative allosteric modulator of the receptor. Replacement of FzM1 thiophene with a carboxylic moiety induces a molecular switch in the lead and transforms the molecule into an activator of WNT signaling. We here show that, in the absence of any WNT ligand, FzM1.8 binds to FZD4, promotes recruitment of heterotrimeric G proteins, and biases WNT signaling toward a noncanonical route that involves PI3K. Finally, in colon cancer cells, we prove that the FZD4/PI3K axis elicited by FzM1.8 preserves stemness and promotes proliferation of undifferentiated cells.

中文翻译：

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WNT受体的负变构调节剂卷曲4开关变构激动剂。

WNT途径将信号事件的网络互连，涉及从器官发生到组织体内平衡的大量细胞过程。尽管具有重要意义，但直接靶向WNT受体的卷曲蛋白家族成员的有机药物的存在阻碍了涉及信号传导的整个生物领域的发展。我们在这里介绍了FzM1.8，这是一种小分子，用作卷曲蛋白受体FZD4的变构激动剂。FzM1.8源自受体的负变构调节剂FzM1。用羧基部分取代FzM1噻吩可诱导先导分子转换并将分子转化为WNT信号转导的激活剂。我们在这里显示，在没有任何WNT配体的情况下，FzM1.8与FZD4结合，促进异源三聚体G蛋白的募集，并将WNT信令偏向涉及PI3K的非规范路由。最后，在结肠癌细胞中，我们证明了由FzM1.8引发的FZD4 / PI3K轴保留了干细胞并促进了未分化细胞的增殖。