Abstract 2520: Novel inhibitors of β-catenin

Abstract

Abstract β-catenin is a key player of the WNT pathway; its aberrant regulation is associated with the onset and progression of numerous types of cancer. β-catenin is therefore an attractive drug target but direct inhibition of β-catenin is a challenging approach toward suppression of β-catenin-driven tumorigenesis. Ideal drug candidates should specifically target nuclear β-catenin, leaving its cytoplasmic and cell junctional functions intact. We have identified several drug-like candidate β-catenin inhibitors using a robust screening method against four allosteric binding sites of β-catenin (TCF4, BCL9 and two novel sites). We show that these inhibitors significantly reduce proliferation of a panel of human β-catenin-driven cancer cell lines, and repress the expression of β-catenin-induced target genes. They cause a shift in the melting temperature of the purified β-catenin protein. We also show that the candidate compounds reduce levels of β-catenin in the nucleus and block β-catenin-driven oncogenic transformation in cell culture. We consider these novel β-catenin inhibitors promising leads that should be further investigated for their molecular mechanism of action and for their potential development as therapeutic drugs. Key words: β-catenin, oncogene, therapeutic, target, small molecule, protein-protein interaction This work was supported by NIH Grant R01 CA078230. This is abstract 26043 of The Scripps Research Institute. Citation Format: Elmar Nurmemmedov, Anton Cheltsov, Peter K. Vogt. Novel inhibitors of β-catenin. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2520. doi:10.1158/1538-7445.AM2014-2520