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

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.