Institute of Crystallography - CNR

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

Despite intensive efforts, no inhibitors of the Wnt/beta-catenin signaling pathway have been approved so far for the clinical treatment of cancer. We synthesized novel N-(heterocyclylphenyl)benzenesulfonamides as beta-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 beta-catenin and Tcf-4. The crystallographic analysis of the beta-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 beta-catenin inhibitors as anticancer agents.

ACS pharmacology & translational science
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Nalli, Marianna; Di Magno, Laura; Wen, Yichao; Liu, Xin; D'Ambrosio, Michele; Puxeddu, Michela; Parisi, Anastasia; Sebastiani, Jessica; Sorato, Andrea; Coluccia, Antonio; Ripa, Silvia; Di Pastena, Fiorella; Capelli, Davide; Montanari, Roberta; Masci, Domiziana; Urbani, Andrea; Naro, Chiara; Sette, Claudio; Orlando, Viviana; D'Angelo, Sara; Biagioni, Stefano; Bigogno, Chiara; Dondio, Giulio; Pastore, Arianna; Stornaiuolo, Mariano; Canettieri, Gianluca; Liu, Te; Silvestri, Romano; La Regina, Giuseppe
Authors IC CNR