Wnt / beta-catenin
Wnt family members are secreted ligands that have numerous roles in development and adult tissue homeostasis. They modulate gene expression programs that impact proliferation, cell fate and morphogenesis. The canonical Wnt signaling pathway operates througha negative control mechanism - when Wnt signaling is absent, a destruction complex in the cytoplasm degrades the transcription factor β-catenin, without which the gene expression driven by Wnt signaling does not occur. In normal, healthy cells when Wnt is present, appropriately regulated amounts of β-catenin move from the cytoplasm into the nucleus where β-catenin forms a complex with several other proteins through protein-protein interactions (PPIs). These PPIs drive expression of genes to signal, amongst other things, cell growth and proliferation. Wnt signaling is particularly important in actively self-renewing tissues, such as the intestinal endothelium.
Mutations that permanently activate the transcriptional program of Wnt signaling are frequent in several malignancies, including about 90% of colorectal cancers. The majority of such mutations affect genes of the β-catenin destruction complex (APC &Axin) or the β-catenin residues critical for ubiquitination and proteosomal degradation. When present, these mutations result in increased levels of β-catenin and aberrant, constitutive transcription of the genes controlling cell proliferation, leading to oncogenesis.
Circle is developing cell-permeable macrocyclic peptides that specifically disrupt PPIs involving β-catenin, and which thereby inhibit the oncogenic transcription program. Circle will develop these macrocycles to treat cancers that are dependent on aberrant β-catenin signaling, such as metastatic colorectal cancer.