LRP5 antagonist BI 905681

An antagonist of the lipoprotein receptor-related protein (LRP) 5, with potential antineoplastic and immunomodulating activities. Upon administration, LRP5 antagonist BI 905681 targets and binds to LRP5, thereby blocking the binding of Wnt ligands to LRP5. This prevents the formation of the serpentine receptor Frizzled (FZD)-Wnt-LRP5 trimeric complex and prevents the inactivation of the beta-catenin degradation complex, which leads to beta-catenin degradation. This inhibits the Wnt/beta-catenin signaling pathway, prevents the beta-catenin-mediated activation of Wnt target genes, and inhibits the proliferation and survival of Wnt/beta-catenin-driven tumor cells. In addition, inhibition of Wnt signaling by BI 905681 prevents Wnt-mediated immune escape, thereby re-activating the immune system, specifically inducing the activation of dendritic cells (DCs) and activation as well as infiltration of cytotoxic T cells into the tumor tissue. The FZD-Wnt-LRP5 trimeric complex induces phosphorylation of LRP5 intracellular domain leading to inactivation of the beta-catenin degradation complex, allowing beta-catenin accumulation; stabilized beta-catenin enters the nucleus and acts as a transcriptional activator of Wnt target genes. Wnt/beta-catenin signaling plays a key role in tumor cell proliferation and survival, and resistance to immunotherapy.