Novel N-(Heterocyclylphenyl)benzensulfonamide Sharing an Unreported Binding Site with T-Cell Factor 4 at the β-Catenin Armadillo Repeats Domain as an Anticancer Agent

• DOI: 10.1021/acsptsci.3c00092
• Publication Date: 2023-07-03T17:50:32Z
• Authors: Marianna Nalli; Laura Di Magno; Yichao Wen; Xin Liu; Michele D’Ambrosio; Michela Puxeddu; Anastasia Parisi; Jessica Sebastiani; Andrea Sorato; Antonio Coluccia; Silvia Ripa; Fiorella Di Pastena; Davide Capelli; Roberta Montanari; Domiziana Masci; Andrea Urbani; Chiara Naro; Claudio Sette; Viviana Orlando; Sara D’Angelo; Stefano Biagioni; Chiara Bigogno; Giulio Dondio; Arianna Pastore; Mariano Stornaiuolo; Gianluca Canettieri; Te Liu; Romano Silvestri; Giuseppe La Regina
• Keywords: crystal structure; T-cell factor; c-MYC; sulfonamide; colorectal cancer; beta-catenin; β-catenin; c-MYC; T-cell factor; colorectal cancer; sulfonamide; crystal structure; 3. Good health

Despite intensive efforts, no inhibitors of the Wnt/β-catenin signaling pathway have been approved so far for the clinical treatment of cancer. We synthesized novel N-(heterocyclylphenyl)benzenesulfonamides as β-catenin inhibitors. Compounds 5-10 showed strong inhibition of the luciferase activity. Compounds 5 and 6 inhibited the MDA-MB-231, HCC1806, and HCC1937 TNBC cells. Compound 9 induced in vitro cell death in SW480 and HCT116 cells and in vivo tumorigenicity of a human colorectal cancer line HCT116. In a co-immunoprecipitation study in HCT116 cells transfected with Myc-tagged T-cell factor 4 (Tcf-4), compound 9 abrogated the association between β-catenin and Tcf-4. The crystallographic analysis of the β-catenin Armadillo repeats domain revealed that compound 9 and Tcf-4 share a common binding site within the hotspot binding region close to Lys508. To our knowledge, compound 9 is the first small molecule ligand of this region to be reported. These results highlight the potential of this novel class of β-catenin inhibitors as anticancer agents.