frizzled-8 Inhibitors

Frizzled-8 inhibitors represent a class of compounds that can interfere with the Wnt signaling pathway, to which the Frizzled family of receptors is central. These compounds are not direct antagonists of the Frizzled-8 receptor but instead target various proteins that participate in the pathway, resulting in the downregulation of the receptor's activity. For instance, inhibitors such as IWP-2 and LGK-974 obstruct the activity of Porcupine, an enzyme crucial for the palmitoylation and subsequent secretion of Wnt proteins. Without active Wnt proteins, the Frizzled-8 receptor cannot initiate signal transduction, effectively silencing its downstream effects.Further along the pathway, compounds like XAV-939 and JW 55 target the β-catenin destruction complex. XAV-939 stabilizes Axin, a component of this complex, thereby promoting the degradation of β-catenin, a central mediator in the Wnt/Frizzled-8 pathway. Without β-catenin, the transcription of Wnt target genes is impaired. Other molecules, such as ICG-001 and FH535, disrupt downstream signaling by modulating the interactions of β-catenin with its transcriptional co-activators or by inhibiting PPARs, demonstrating the multi-faceted approach these inhibitors can take. In summary, these chemical entities exploit various regulatory checkpoints within the Wnt/Frizzled-8 pathway, thereby serving as indirect inhibitors of Frizzled-8.