Human BCL9 blocking peptide

Structure-based optimization was conducted to improve the potency, selectivity, and cell-based activities of beta-catenin/B-cell lymphoma 9 (BCL9) inhibitors based on the 4'-fluoro-N-phenyl-[1,1'-biphenyl]-3-carboxamide scaffold, which was designed to mimic the side chains of the hydrophobic a-helical hot spots at positions i, i + 3, and i + 7. Compound 29 was found to disrupt the beta-catenin/BCL9 protein-protein interaction (PPI) with a K-i of 0.47 mu M and >1900-fold selectivity for beta-catenin/BCL9 over beta-catenin/E-cadherin PPIs. The proposed binding mode of new inhibitors was consistent with the results of site-directed mutagenesis and structure-activity relationship studies. Cell-based studies indicated that 29 disrupted the beta-catenin/BCL9 interaction without affecting the beta-catenin/E-cadherin interaction, selectively suppressed transactivation of Wnt/beta-catenin signaling, downregulated expression of Wnt target genes, and inhibited viability of Wnt/beta-catenin-dependent cancer cells in dose-dependent manners. A comparison of the biochemical and cell-based assay results offered the directions for future inhibitor optimization.

Microdeletion and microduplication copy number variations are found in patients with autism spectrum disorder and in a number of cases they include genes that are involved in the canonical Wnt signaling pathway (for example, FZD9, BCL9 or CDH8). Association studies investigating WNT2, DISC1, MET, DOCK4 or AHI1 also provide evidence that the canonical Wnt pathway might be affected in autism. Prenatal medication with sodium-valproate or antidepressant drugs increases autism risk. In animal studies, it has been found that these medications promote Wnt signaling, including among others an increase in Wnt2 gene expression. Notably, the available genetic information indicates that not only canonical Wnt pathway activation, but also inhibition seems to increase autism risk. The canonical Wnt pathway plays a role in dendrite growth and suboptimal activity negatively affects the dendritic arbor. In principle, this provides a logical explanation as to why both hypo-and hyperactivity may generate a similar set of behavioral and cognitive symptoms. However, without a validated biomarker to stratify for deviant canonical Wnt pathway activity, it is probably too dangerous to treat patients with compounds that modify pathway activity.