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Wnt pathway inhibitors and activators modulate signaling by secreted Wnt proteins through β-catenin and its partners. Without a Wnt signal, a destruction complex built on axin phosphorylates β-catenin and marks it for proteasomal degradation. Tankyrase inhibition stabilizes axin, so XAV 939 and IWR-1-endo promote β-catenin breakdown and reduce Wnt target gene expression. LGK-974 and Wnt-C59 inhibit porcupine (PORCN), the acyltransferase that lipid-modifies Wnt proteins before their secretion. ICG-001 blocks the binding of β-catenin to the coactivator of cyclic adenosine monophosphate response element-binding protein (CREB), known as CREB-binding protein (CBP). BML-284 acts in the opposite direction, as a Wnt agonist that induces β-catenin-dependent transcription.
xStAx-VHLL is a PROTAC degrader targeting β-catenin, promoting its ubiquitination and proteasomal degradation. It effectively inhibits the Wnt/β-catenin signaling pathway and suppresses proliferation of colon cancer cells, demonstrating anti-tumor activity.
