New N-(heterocyclylphenyl)benzenesulfonamides as beta-catenin inhibitors

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.1 In crystallographic studies of the beta-catenin armadillo repeats domain, compound 1 superimposed to Tcf-4 (PDB ID 2GL7) highlighting a common binding site within the hotspot binding region close to Lys508. To our knowledge, compound 1 is the first small molecule ligand of this region to be reported. In co-immunoprecipitation study in cells transfected with Myc-tagged Tcf-4, compound 1 abrogated the association between beta-catenin and Tcf-4. Compound 1 induced in vitro cell death in SW480 and HCT116 cells and in vivo tumorigenicity of a human colorectal cancer line HCT-116. These results highlight the potential of this novel class of beta-catenin inhibitors as anticancer agents. References 1. Nalli, M.; Di Magno, L.; Wen, Y.; Liu, X.; D'Ambrosio, M.; Puxeddu, M.; Parisi, A.; Coluccia, A.; Ripa, S.; Di Pastena, F.; Fionda, C.; Capelli, D.; Montanari, R.; Masci, D.; Urbani, A.; Naro, C.; Sette, C.; Orlando, V.; D'Angelo, S.; Biagioni, S.; Bigogno, C.; Dondio, G.; Stornaiuolo, M.; Canettieri, G.; Liu, T.; Silvestri, R.; La Regina, G. J. Med. Chem. 2023, submitted.