E7386: A Pioneering Oral CBP/Beta-Catenin Modulator Targeting Wnt Pathway in Cancer Therapy

The study focuses on the development of a new oral molecule, E7386, which is designed to inhibit the Wnt/beta-catenin signaling pathway, a common target in cancer therapy due to its frequent mutations in various cancers. E7386, created by PRISM Pharma, targets the interaction between beta-catenin and its transcriptional coactivator, CBP, to modulate the Wnt pathway. The compound was found to disrupt the beta-catenin/CBP interaction and suppress the canonical Wnt signaling pathway in a dose-dependent manner, with IC50 values of 55 nmol/L and 73 nmol/L for two different cell lines. It also modulated the expression of Wnt-related genes, similar to the effects of beta-catenin knockdown.

In vivo testing in ApcMin/+ mice, which develop intestinal polyps due to Wnt/beta-catenin pathway activation, showed that E7386 significantly reduced polyp numbers in a dose-dependent manner. The compound also altered the expression of Wnt-related genes in the whisker follicle of the mice. Furthermore, E7386 demonstrated potent anti-proliferative activity against cancer cell lines with mutated Wnt signaling pathway components and exhibited significant antitumor effects in a human tumor cell line xenograft model with an APC mutation.

E7386 is a novel, first-in-class CBP/beta-catenin modulator that has shown strong inhibitory effects on the aberrant activation of the Wnt/beta-catenin signaling pathway, offering potential as an anticancer agent. The research was presented at the American Association for Cancer Research Annual Meeting in 2017, with the study abstract published in the Cancer Research journal.