FRAT1 Inhibitors

FRAT1 inhibitors encompass a diverse group of chemicals that indirectly downregulate the activity of the FRAT1 protein by targeting various components of the Wnt/β-catenin signaling pathway. This pathway is a complex cellular communication system that is pivotal in regulating cell fate, proliferation, and migration. The relevance of these inhibitors stems from their ability to modulate the Wnt pathway, which FRAT1 is known to promote by acting as a positive regulator. By inhibiting certain aspects of the Wnt/β-catenin signaling cascade, these compounds can reduce the functional output of FRAT1. The class of FRAT1 inhibitors includes small molecules that can either interrupt the post-translational modification of Wnt ligands, such as C59 and LGK-974 which inhibit the enzyme Porcupine, or disrupt the nuclear actions of β-catenin, which is the central mediator of Wnt signaling transduction. Compounds like ICG-001 and PNU-74654 achieve this by inhibiting the interaction between β-catenin and its co-factors, such as the CREB-binding protein and T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) family of transcription factors, respectively. This prevents the transcription of Wnt target genes, which are crucial for exerting the pathway's effects. Other inhibitors, like XAV-939 and JW55, target the enzyme tankyrase, which facilitates the poly-ADP-ribosylation and subsequent proteasomal degradation of Axin, a negative regulator of the Wnt pathway. By stabilizing Axin, these inhibitors promote the degradation of β-catenin, reducing its cytoplasmic levels and thereby its nuclear signaling capabilities.